Tetrahydrothiopyrano pyrazole cannabinoid modulators

ABSTRACT

The invention relates to a CB modulator compound of Formula (I)  
                 
or a pharmaceutically acceptable form thereof and a method for use in treating, ameliorating or preventing a CB receptor mediated syndrome, disorder or disease.

CROSS REFERENCE TO RELATED APPLICATIONS

This present application claims benefit of U.S. Provisional PatentApplication Ser. No. 60/666,898, filed Mar. 31, 2005, which isincorporated herein by reference in its entirety and for all purposes.

BACKGROUND OF THE INVENTION

Before the discovery of the cannabinoid CB1 and CB2 receptors, the termcannabinoid (CB) was used to describe the biologically active componentsof cannabis sativa, the most abundant of which aredelta-9-tetrahydrocannabinol (THC) and cannabidiol.

THC is a moderately potent partial agonist of the CB1 and CB2 receptorsand is considered the “classical cannabinoid,” a term now used to referto other analogues and derivatives that are structurally related to thetricyclic dibenzopyran THC core. The term “non-classical cannabinoid”refers to CB agonists structurally related to cannabidiol.

Pharmacological investigations have concentrated on selective CBreceptor modulators of the pyrazole structural class, which include SR141716A (the monohydrochloride salt of SR 141716) and SR 144528. SR141716A was the first potent and selective CB1 receptor antagonist.

Pyrazole CB modulators are among the many different structural classeswhich have aided the development of CB pharmacology, have helped todetermine the biological effects mediated by the CB receptors, will leadto further refinement of current compounds, and will be a source of newchemical classes in the future.

Certain compounds (including SR 141716, SR 144528 and the like) thatwere originally classified as selective antagonists are now consideredto act as “inverse agonists” rather than pure antagonists. Inverseagonists have the ability to decrease the constitutive level of receptoractivation in the absence of an agonist instead of only blocking theactivation induced by agonist binding at the receptor. The constitutiveactivity of CB receptors has important implications since there is alevel of continuous signaling by CB1 even in the absence of an agonist.For example, SR 141716A increases CB1 protein levels and sensitizescells toward agonist action, thus indicating that inverse agonists maybe another class of ligands used to modulate the endocannabinoid systemand the downstream signaling pathways activated by cannabinoidreceptors.

Advances in the synthesis of CB and cannabimimetic ligands havefurthered the development of receptor pharmacology and provided evidencefor the existence of additional CB receptor sub-types. However, thereremains an ongoing need for the identification and development of smallmolecule CB1 or CB2 receptor modulators for the treatment of a varietyof CB receptor modulated syndromes, disorders, and diseases.

All documents cited herein are incorporated by reference.

SUMMARY OF THE INVENTION

This invention is directed to tetrahydrothiopyrano pyrazole CB modulatorcompounds and a method for use in treating, ameliorating or preventing aCB receptor mediated syndrome, disorder or disease.

The invention relates to a CB modulator compound of Formula (I)

or a pharmaceutically acceptable form thereof and a method for use intreating, ameliorating or preventing a CB receptor mediated syndrome,disorder or disease.

DESCRIPTION OF THE INVENTION

This invention is directed to a compound of Formula (I):

wherein

-   the dashed lines between positions 2-3 and positions 3a-7a in    Formula (I) each represent the location for a double bond when X₁R₁    is present;-   the dashed lines between positions 3-3a and positions 7a-1 in    Formula (I) each represent the location for a double bond when X₂R₂    is present;-   the dashed line between position 7 and X₄R₄ in Formula (I)    represents the location for a double bond;-   X is sulfur, sulfoxo or sulfonyl;-   X₁ is absent or is lower alkylene;-   X₂ is absent or is lower alkylene;-   wherein only one of X₁R₁ and X₂R₂ are present;-   X₃ is absent or is lower alkylene or lower alkylidene;-   when the dashed line between position 7 and X₄R₄ is absent, then X₄    is absent or is lower alkylene;-   when the dashed line between position 7 and X₄R₄ is present, then X₄    is absent;-   R₁ is hydrogen, aryl, C₃-C₁₂ cycloalkyl, or heterocyclyl, wherein    each of aryl, C₃-C₁₂ cycloalkyl, or heterocyclyl is optionally    substituted at one or more positions by halogen, lower alkyl,    hydroxy or lower alkoxy;-   R₂ is hydrogen, aryl, C₃-C₁₂ cycloalkyl, or heterocyclyl, wherein    each of aryl, C₃-C₁₂ cycloalkyl, or heterocyclyl is optionally    substituted at one or more positions by halogen, lower alkyl,    hydroxy or lower alkoxy;-   R₃ is —C(O)-heterocyclyl or -Z-N(R₆)-Z₁R₇ (optionally substituted on    heterocyclyl by one or more hydroxy, halogen, amino, lower alkyl,    carboxy, alkoxycarbonyl, lower alkoxy, lower alkoxy-lower alkylene-,    hydroxy-alkylene-, aryloxy or arylalkoxy);-   when the dashed line between position 7 and X₄R₄ is absent, then R₄    is hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen, aryl    (optionally substituted on aryl at one or more positions by hydroxy,    lower alkyl, lower alkoxy or halogen), heterocyclyl (optionally    substituted on heterocyclyl at one or more positions by hydroxy,    lower alkyl, lower alkoxy or halogen) or C₃-C₁₂ cycloalkyl    (optionally substituted on C₃-C₁₂ cycloalkyl at one or more    positions by hydroxy, lower alkyl, lower alkoxy or halogen);-   when the dashed line between position 7 and X₄R₄ is present, then R₄    is CH-aryl (optionally substituted on aryl at one or more positions    by hydroxy, lower alkyl, lower alkoxy or halogen) or CH-heterocyclyl    (optionally substituted on heterocyclyl at one or more positions by    hydroxy, lower alkyl, lower alkoxy or halogen);-   R₆ and R₇ are each individually hydrogen, lower alkyl, —NR₈R₉, aryl    (optionally substituted on aryl by one or more hydroxy, halogen,    lower alkyl, carboxy, alkoxycarbonyl, lower alkoxy,    hydroxy-alkylene-, aryloxy or arylalkoxy), C₃-C₁₂ cycloalkyl    (optionally substituted on C₃-C₁₂ cycloalkyl by one or more hydroxy,    halogen, amino, lower alkyl, carboxy, alkoxycarbonyl, lower alkoxy,    hydroxy, alkylene-, aryloxy, arylalkoxy or lower alkylene) or    heterocyclyl (optionally substituted on heterocyclyl by one or more    hydroxy, halogen, amino, lower alkyl, carboxy, alkoxycarbonyl, lower    alkoxy, lower alkoxy-lower alkylene-, hydroxy-alkylene-, aryloxy or    arylalkoxy);-   R₈ and R₉ are each individually hydrogen, alkyl, heterocyclyl,    C₃-C₁₂ cycloalkyl, or aryl (optionally substituted on aryl by one or    more lower alkyl, hydroxy, alkoxy, halogen, heterocyclyl or    aryl-lower alkylene-);-   Z is carbonyl or sulfonyl;-   Z₁ is absent or is lower alkylene optionally substituted at one or    more positions by halogen, hydroxy, lower alkoxy, carboxy or lower    alkoxycarbonyl;    or a pharmaceutically acceptable salt, isomer, prodrug, metabolite    or polymorph thereof.

An example of the present invention is a compound of Formula (I) whereinX₁ is absent or is lower alkylene and R₁ is hydrogen, C₃-C₁₂ cycloalkylor aryl (optionally substituted on aryl at one or more positions bylower alkyl, lower alkoxy or halogen).

An example of the present invention is a compound of Formula (I) whereinwhen the dashed line between position 7 and X₄ is absent, then X₄ isabsent or is lower alkylene and R₄ is hydrogen, hydroxy, lower alkyl,lower alkoxy, halogen, aryl (optionally substituted on aryl at one ormore positions by lower alkoxy or halogen), heterocyclyl (optionallysubstituted on heterocyclyl at one or more positions by halogen) orC₃-C₈ cycloalkyl.

An example of the present invention is a compound of Formula (I) whereinwhen the dashed line between positions 7 and X₄R₄ is absent, then X₄ isabsent and R₄ is hydrogen.

An example of the present invention is a compound of Formula (I) whereinX₃ is absent or is lower alkylidene; R₃ is —C(O)-heterocyclyl or-Z-N(R₆)-Z₁R₇ (optionally substituted on heterocyclyl by one or morehydroxy, halogen, amino, lower alkyl, carboxy, alkoxycarbonyl, loweralkoxy, lower alkoxy-lower alkylene-, hydroxy-alkylene-, aryloxy orarylalkoxy); Z is carbonyl or sulfonyl; Z₁ is absent or is loweralkylene; and R₆ and R₇ are each individually hydrogen, lower alkyl,—NR₈R₉, aryl (optionally substituted on aryl by one or more hydroxy,halogen, lower alkyl, carboxy, alkoxycarbonyl, lower alkoxy,hydroxy-alkylene-, aryloxy or arylalkoxy), C₃-C₁₂ cycloalkyl (optionallysubstituted on C₃-C₁₂ cycloalkyl by one or more hydroxy, halogen, amino,lower alkyl, carboxy, alkoxycarbonyl, lower alkoxy, hydroxy-alkylene-,aryloxy, arylalkoxy or lower alkylene) or heterocyclyl (optionallysubstituted on heterocyclyl by one or more hydroxy, halogen, amino,lower alkyl, carboxy, alkoxycarbonyl, lower alkoxy, lower alkoxy-loweralkylene-, hydroxy-alkylene-, aryloxy or arylalkoxy), wherein R₈ and R₉are each individually hydrogen, alkyl, heterocyclyl, C₃-C₁₂ cycloalkylor aryl (optionally substituted on aryl by one or more lower alkyl,hydroxy, alkoxy, halogen, heterocyclyl or aryl-lower alkylene-).

An example of the present invention is a compound of Formula (I) whereinX₃ is absent or is lower alkylidene; R₃ is —C(O)-heterocyclyl or-Z-N(R₆)-Z₁R₇; Z is carbonyl or sulfonyl; Z₁ is absent or is loweralkylene; and R₆ and R₇ are each individually hydrogen, lower alkyl,—NR₈R₉, aryl (optionally substituted on aryl by one or more hydroxy,halogen, lower alkyl, lower alkoxy or hydroxy-alkylene-), C₃-C₁₂cycloalkyl (optionally substituted on C₃-C₁₂ cycloalkyl by one or morehydroxy, halogen, amino, lower alkyl, carboxy, alkoxycarbonyl, loweralkoxy or hydroxy-alkylene-), or heterocyclyl (optionally substituted onheterocyclyl by one or more hydroxy, halogen, amino, lower alkyl,carboxy, alkoxycarbonyl, lower alkoxy, lower alkoxy-lower alkylene- orhydroxy-alkylene-), wherein R₈ and R₉ are each individually hydrogen,alkyl, heterocyclyl, C₃-C₁₂ cycloalkyl or aryl (optionally substitutedon aryl by one or more lower alkyl, hydroxy, alkoxy or halogen).

An example of the present invention is a compound of Formula (I) whereinX₃ is absent or is lower alkylidene; R₃ is —C(O)-heterocyclyl or-Z-N(R₆)-Z₁R₇; Z is carbonyl or sulfonyl; Z, is absent or is loweralkylene; and Rr and R₇ are each individually hydrogen, lower alkyl,—NR₈R₉, aryl, C₃-C₁₂ cycloalkyl (optionally substituted on C₃-C₁₂cycloalkyl by one or more hydroxy, lower alkyl or alkoxycarbonyl), orheterocyclyl (optionally substituted on heterocyclyl by one or morelower alkyl, alkoxycarbonyl, lower alkoxy-lower alkylene- orhydroxy-alkylene-), wherein R₈ and R₉ are each individually hydrogen,alkyl, C₃-C₁₂ cycloalkyl or aryl (optionally substituted on aryl by oneor more halogen).

An example of the present invention is a compound of Formula (I) whereinX₂ is absent or is lower alkylene; and, R₂ is C₃-C₁₂ cycloalkyl or aryl(optionally substituted on aryl at one or more positions by lower alkyl,lower alkoxy or halogen).

An example of the present invention is a compound of Formula (I) whereinwhen the dashed line between position 7 and X₄R₄ is present, then X₄ isabsent and R₄ is CH-aryl (optionally substituted on aryl at one or morepositions by hydroxy, lower alkyl, lower alkoxy or halogen) orCH-heterocyclyl (optionally substituted on heterocyclyl at one or morepositions by hydroxy, lower alkyl, lower alkoxy or halogen).

An example of the present invention is a compound of Formula (I) whereinwhen the dashed line between position 7 and X₄R₄ is present, then X₄ isabsent and R₄ is CH-aryl (optionally substituted on aryl at one or morepositions by lower alkyl, lower alkoxy or halogen) or CH-heterocyclyl(optionally substituted on heterocyclyl at one or more positions bylower alkyl, lower alkoxy or halogen).

An example of the present invention is a compound of Formula (I) whereinwhen the dashed line between position 7 and X₄R₄ is present, then X₄ isabsent and R₄ is CH-phenyl, CH-thienyl or CH-furyl (optionallysubstituted on phenyl, thienyl or furyl at one or more positions bylower alkyl, lower alkoxy or halogen).

An example of the present invention is a compound of Formula (I) whereinX is sulfur, sulfoxo or sulfonyl; X₁ is absent or is lower alkylene; R₁is hydrogen, C₃-C₁₂ cycloalkyl or aryl (optionally substituted on arylat one or more positions by lower alkyl, lower alkoxy or halogen); whenthe dashed line between positions 7 and X₄R₄ is absent, then X₄ isabsent and R₄ is hydrogen; X₃ is absent or is lower alkylidene; R₃ is—C(O)-heterocyclyl or -Z-N(R₆)-Z₁R₇; Z is carbonyl or sulfonyl; Z₁ isabsent or is lower alkylene; R₆ and R₇ are each individually hydrogen,lower alkyl, —NR₈R₉, aryl, C₃-C₁₂ cycloalkyl (optionally substituted onC₃-C₁₂ cycloalkyl by one or more hydroxy, lower alkyl or alkoxycarbonyl)or heterocyclyl (optionally substituted on heterocyclyl by one or morelower alkyl, alkoxycarbonyl, lower alkoxy-lower alkylene- orhydroxy-alkylene-), wherein R₈ and R₉ are each individually hydrogen,alkyl, C₃-C₁₂ cycloalkyl or aryl (optionally substituted on aryl by oneor more halogen); X₂ is absent or is lower alkylene; R₂ is C₃-C₁₂cycloalkyl or aryl (optionally substituted on aryl at one or morepositions by lower alkyl, lower alkoxy or halogen); and, when the dashedline between position 7 and X₄R₄ is present, then X₄ is absent and R₄ isCH-phenyl, CH-thienyl or CH-furyl (optionally substituted on phenyl,thienyl or furyl at one or more positions by lower alkyl, lower alkoxyor halogen).

An example of the invention is a compound of Formula (Ia)

wherein X₁R₁, X₃R₃, and X₄R₄ are dependently selected from Cpd X₁R₁ X₃R₃X₄R₄ 1 CH₂-phenyl C(O)NH—CH(phenyl)-R—CH₃ H 3 CH₂-phenylCH═CHSO₂NH—CH(phenyl)-S—CH₃ H 7 CH₂-phenyl CH═CHSO₂NH—CH(phenyl)-R—CH₃ H11 CH₂-phenyl CH═CHSO₂NH—CH(cyclohexyl)-R—CH₃ H 12 CH₂-phenylCH═CHSO₂NH—CH(cyclohexyl)-S—CH₃ H 19 CH₂-phenyl C(O)NH-1,3,3-(CH₃)₃- Hbicyclo[2.2.1]hept-2-yl 32 CH₂-phenyl CH═CHC(O)NH—CH(phenyl)-S—CH₃ H 33CH₂-phenyl CH═CHC(O)NH—CH(phenyl)-R—CH₃ H 38 2,4-F₂-phenylCH═CHSO₂NH—CH(phenyl)-S—CH₃ CH₂-3-F-phenyl 39 2,4-F₂-phenylCH═CHSO₂NH—CH(cyclohexyl)-R—CH₃ CH₂-3-F-phenyl 40 2,4-F₂-phenylCH═CHSO₂NH-piperidin-1-yl CH₂-3-F-phenyl 41 2,4-F₂-phenylCH═CHSO₂NH-morpholin-4-yl CH₂-3-F-phenyl 46 2,4-Cl₂-phenylCH═CHSO₂NH—CH(phenyl)-S—CH₃ CH₂-3-Cl-phenyl 47 HCH═CHSO₂NH—CH(phenyl)-S—CH₃ CH₂-3-F-phenyl 48 HCH═CHSO₂NH—CH(cyclohexyl)-R—CH₃ CH₂-3-F-phenyl 52 2,4-Cl₂-phenylC(O)NHNH-2,4-Cl₂-phenyl (Z)-CH-4-F-phenyl 54 2,4-Cl₂-phenylC(O)NH-piperidin-1-yl (Z)-CH-4-F-phenyl 55 2,4-Cl₂-phenylC(O)-piperidin-1-yl (Z)-CH-4-F-phenyl 56 2,4-Cl₂-phenylC(O)NH-pyrrolidin-1-yl (Z)-CH-4-F-phenyl 57 2,4-Cl₂-phenylC(O)-pyrrolidin-1-yl (Z)-CH-4-F-phenyl 58 2,4-Cl₂-phenylC(O)NH-(1R-2S)-2-OH-indan-1-yl (Z)-CH-4-F-phenyl 59 2,4-Cl₂-phenylC(O)NH-(1S,2R)-2-OH-indan-1-yl (Z)-CH-4-F-phenyl 60 2,4-Cl₂-phenylC(O)NH-(1R,2R)-2-OH-cyclopentyl (Z)-CH-4-F-phenyl 61 2,4-Cl₂-phenylC(O)NH-(1R,2R)-2-OH-cyclohexyl (Z)-CH-4-F-phenyl 62 2,4-Cl₂-phenylC(O)NH—CH(phenyl)-S—CH₃ (Z)-CH-4-F-phenyl 63 2,4-Cl₂-phenylC(O)NH—CH(phenyl)-R—CH₃ (Z)-CH-4-F-phenyl 64 2,4-Cl₂-phenylC(O)NH-4-C(O)OC(CH₃)₃-piperazin-1- (Z)-CH-4-F-phenyl yl 722,4-Cl₂-phenyl C(O)NHCH₂-pyridin-2-yl (Z)-CH-4-F-phenyl 93 4-Cl-phenylC(O)NH-piperidin-1-yl (Z)-CH-4-F-phenyl 94 4-Cl-phenylC(O)NH—CH(phenyl)-R—CH₃ (Z)-CH-4-F-phenyl 102 4-Cl-phenylC(O)NH-pyrrolidin-1-yl (Z)-CH-4-F-phenyl 103 4-Cl-phenylC(O)NH-hexahydro- (Z)-CH-4-F-phenyl cyclopenta[c]pyrrol-2-yl 1112,4-Cl₂-phenyl C(O)NH-2,6-(CH₃)₂-piperidin-1-yl (Z)-CH-4-F-phenyl 1122,4-Cl₂-phenyl C(O)NH-azepan-1-yl (Z)-CH-4-F-phenyl 113 2,4-Cl₂-phenylC(O)NH-4-CH₃-piperazin-1-yl (Z)-CH-4-F-phenyl 114 2,4-Cl₂-phenylC(O)NH-4-(CH₂)₂OH-piperazin-1-yl (Z)-CH-4-F-phenyl 115 2,4-Cl₂-phenylC(O)NHNH-cyclohexyl (Z)-CH-4-F-phenyl 116 2,4-Cl₂-phenylC(O)NH-hexahydro- (Z)-CH-4-F-phenyl cyclopenta[c]pyrrol-2-yl 1222,4-Cl₂-phenyl C(O)NH—(2R)-2-CH₂OCH₃-pyrrolidin- (Z)-CH-4-F-phenyl 1-yl123 2,4-Cl₂-phenyl C(O)NH—(2S)-2-CH₂OCH₃-pyrrolidin- (Z)-CH-4-F-phenyl1-yl 127 2,4-Cl₂-phenyl C(O)NH-(R—CH)(pyridin-2-yl)-CH₃(Z)-CH-4-F-phenyl 129 2,4-Cl₂-phenyl C(O)NH—CH(phenyl)-R—CH₃(Z)-CH-4-Br-phenyl 130 2,4-Cl₂-phenyl C(O)NH-piperidin-1-yl(Z)-CH-4-Br-phenyl

An example of the invention is a compound of Formula (Ib)

wherein X₂R₂, X₃R₃, and X₄R₄ are dependently selected from Cpd X₂R₂ X₃R₃X₄R₄ 2 CH₂-phenyl CH═CHSO₂NH—CH(phenyl)-R—CH₃ H 5 CH₂-phenylCH═CHSO₂NH—CH(phenyl)-S—CH₃ H 6 CH₂-phenylCH═CHSO₂NH—CH(cyclohexyl)-R—CH₃ H 8 CH₂-phenylCH═CHSO₂NH—CH(cyclohexyl)-S—CH₃ H 78 2,4-Cl₂-phenylC(O)NH—CH(phenyl)-R—CH₃ (Z)-CH-4-F-phenyl 88 2,4-Cl₂-phenylC(O)NH-piperidin-1-yl (Z)-CH-4-F-phenyl 89 2,4-Cl₂-phenylC(O)NH—CH(cyclohexyl)-R—CH₃ (Z)-CH-4-F-phenyl 90 2,4-Cl₂-phenylC(O)NH—CH(cyclohexyl)-S—CH₃ (Z)-CH-4-F-phenyl 91 2,4-Cl₂-phenylC(O)NH—CH(phenyl)-S—CH₃ (Z)-CH-4-F-phenyl 92 2,4-Cl₂-phenylC(O)NH-hexahydro-cyclopenta[c]pyrrol- (Z)-CH-4-F-phenyl 2-yl

An example of the invention is a compound of Formula (Ic)

wherein X₁R₁, X₃R₃, and X₄R₄ are dependently selected from Cpd X₁R₁ X₃R₃X₄R₄ 21 CH₂-phenyl C(O)NH-1,3,3-(CH₃)₃- H bicyclo[2.2.1]hept-2-yl 25CH₂-phenyl CH═CHSO₂NH—CH(cyclohexyl)-CH₃ H 29 CH₂-phenylCH═CHSO₂NH—CH(phenyl)-CH₃ H 30 CH₂-phenyl CH═CHSO₂NH—CH(phenyl)-R—CH₃ H31 CH₂-phenyl CH═CHSO₂NH—CH(phenyl)-S—CH₃ H 34 CH₂-phenylCH═CHC(O)NH—CH(phenyl)-S—CH₃ H 35 CH₂-phenylCH═CHC(O)NH—CH(phenyl)-R—CH₃ H 74 2,4-Cl₂-phenyl C(O)NH—CH(phenyl)-S—CH₃(Z)-CH-4-F-phenyl 75 2,4-Cl₂-phenyl C(O)NH—CH(phenyl)-R—CH₃(Z)-CH-4-F-phenyl 76 2,4-Cl₂-phenyl C(O)NH-(1R,2R)-2-OH-cyclopentyl(Z)-CH-4-F-phenyl 77 2,4-Cl₂-phenyl C(O)NHNH-2,4-Cl₂-phenyl(Z)-CH-4-F-phenyl 79 2,4-Cl₂-phenyl C(O)NH-piperidin-1-yl(Z)-CH-4-F-phenyl 80 2,4-Cl₂-phenyl C(O)NHCH₂-pyridin-2-yl(Z)-CH-4-F-phenyl 96 4-Cl-phenyl C(O)NH-piperidin-1-yl (Z)-CH-4-F-phenyl

An example of the invention is a compound of Formula (Id)

wherein X₂R₂ and X₃R₃ are dependently selected from Cpd X₂R₂ X₃R₃ 22CH₂-phenyl CH═CHSO₂NH—CH(phenyl)-CH₃ 23 CH₂-phenylCH═CHSO₂NH—CH(phenyl)-R—CH₃ 24 CH₂-phenyl CH═CHSO₂NH—CH(phenyl)-S—CH₃ 26CH₂-phenyl CH═CHSO₂NH—CH(cyclohexyl)-CH₃ 27 CH₂-phenylCH═CHSO₂NH—CH(cyclohexyl)-R—CH₃ 28 CH₂-phenylCH═CHSO₂NH—CH(cyclohexyl)-S—CH₃

An example of the invention is a compound of Formula (Ie)

wherein X₁R₁, X₃R₃, and X₄R₄ are dependently selected from Cpd X₁R₁ X₃R₃X₄R₄ 9 CH₂-phenyl CH═CHSO₂NH—CH(phenyl)-R—CH₃ H 13 CH₂-phenylC(O)NH—CH(phenyl)-R—CH₃ H 14 CH₂-phenyl CH═CHSO₂NH—CH(cyclohexyl)-R—CH₃H 15 CH₂-phenyl CH═CHSO₂NH—CH(cyclohexyl)-S—CH₃ H 18 CH₂-phenylCH═CHSO₂NH—CH(phenyl)-S—CH₃ H 20 CH₂-phenyl C(O)NH-1,3,3-(CH₃)₃- Hbicyclo[2.2.1]hept-2-yl 36 CH₂-phenyl CH═CHC(O)NH—CH(phenyl)-S—CH₃ H 37CH₂-phenyl CH═CHC(O)NH—CH(phenyl)-R—CH₃ H 42 2,4-F₂-phenylCH═CHSO₂NH—CH(phenyl)-S—CH₃ CH₂-3-F-phenyl 43 2,4-F₂-phenylCH═CHSO₂NH—CH(cyclohexyl)-R—CH₃ CH₂-3-F-phenyl 44 2,4-F₂-phenylCH═CHSO₂NH-morpholin-4-yl CH₂-3-F-phenyl 45 2,4-F₂-phenylCH═CHSO₂NH-piperidin-1-yl CH₂-3-F-phenyl 49 2,4-F₂-phenylC(O)NH—(2R,3S)-2-C(O)OCH₂CH₃- R—CH₂-3-F-phenyl bicyclo[2.2.1]heptan-3-yl50 2,4-F₂-phenyl C(O)NH—(2R,3S)-2-C(O)OCH₂CH₃- S—CH₂-3-F-phenylbicyclo[2.2.1]heptan-3-yl 51 2,4-F₂-phenylC(O)NH—(1R,2S)-2-OH-indan-1-yl CH₂-3-F-phenyl 53 2,4-Cl₂-phenylC(O)NHNH-2,4-Cl₂-phenyl CH₂-4-F-phenyl 65 2,4-Cl₂-phenylC(O)NH—CH(phenyl)-S—CH₃ (Z)-CH-4-F-phenyl 66 2,4-Cl₂-phenylC(O)NH—CH(phenyl)-R—CH₃ (Z)-CH-4-F-phenyl 67 2,4-Cl₂-phenylC(O)NH—(1R,2R)-2-OH-cyclopentyl (Z)-CH-4-F-phenyl 68 2,4-Cl₂-phenylC(O)NH—(1S,2S)-2-OH-cyclohexyl (Z)-CH-4-F-phenyl 69 2,4-Cl₂-phenylC(O)NH—(1R,2S)-2-OH-indan-1-yl (Z)-CH-4-F-phenyl 70 2,4-Cl₂-phenylC(O)NH—(1S,2R)-2-OH-indan-1-yl (Z)-CH-4-F-phenyl 71 2,4-Cl₂-phenylC(O)NH₂ (Z)-CH-4-F-phenyl 73 2,4-Cl₂-phenyl C(O)NH—CH₂-pyridin-2-yl(Z)-CH-4-F-phenyl 81 2,4-Cl₂-phenyl C(O)NH-piperidin-1-yl(Z)-CH-4-F-phenyl 95 4-Cl-phenyl C(O)NH—CH(phenyl)-R—CH₃(Z)-CH-4-F-phenyl 97 4-Cl-phenyl C(O)NH-hexahydro- (Z)-CH-4-F-phenylcyclopenta[c]pyrrol-2-yl 98 4-Cl-phenyl C(O)-piperidin-1-yl(Z)-CH-4-F-phenyl 99 4-Cl-phenyl C(O)NH-piperidin-1-yl (Z)-CH-4-F-phenyl100 4-Cl-phenyl C(O)NHN(CH₃)-phenyl (Z)-CH-4-F-phenyl 101 2,4-Cl₂-phenylC(O)-piperidin-1-yl (Z)-CH-4-F-phenyl 104 2,4-Cl₂-phenylC(O)NH-hexahydro- (Z)-CH-4-F-phenyl cyclopenta[c]pyrrol-2-yl 1052,4-F₂-phenyl C(O)NH-hexahydro- (Z)-CH-4-F-phenylcyclopenta[c]pyrrol-2-yl 106 2,4-F₂-phenyl C(O)NH-piperidin-1-yl(Z)-CH-4-F-phenyl 107 2,4-Cl₂-phenyl C(O)NH-azepan-1-yl(Z)-CH-4-F-phenyl 108 2,4-Cl₂-phenyl C(O)NH-2,6-(CH₃)₂-piperidin-1-yl(Z)-CH-4-F-phenyl 109 2,4-Cl₂-phenyl C(O)NH-4-CH₃-piperazin-1-yl(Z)-CH-4-F-phenyl 110 2,4-Cl₂-phenyl C(O)NH-4-(CH₂)₂OH-piperazin-1-yl(Z)-CH-4-F-phenyl 117 2,4-Cl₂-phenyl C(O)NH—CH(phenyl)-R—CH₃(Z)-CH-5-Cl-fur-2- yl 118 2,4-Cl₂-phenyl C(O)NH—CH(cyclohexyl)-R—CH₃(Z)-CH-5-Cl-fur-2- yl 119 2,4-Cl₂-phenyl C(O)NH-piperidin-1-yl(Z)-CH-5-Cl-fur-2- yl 120 2,4-Cl₂-phenyl C(O)NH-azepan-1-yl(Z)-CH-5-Cl-fur-2- yl 121 2,4-Cl₂-phenyl C(O)NH-hexahydro-(Z)-CH-5-Cl-fur-2- cyclopenta[c]pyrrol-2-yl yl 124 2,4-Cl₂-phenylC(O)NH—(R—CH)(pyridin-2-yl)-CH₃ (Z)-CH-4-F-phenyl 125 2,4-Cl₂-phenylC(O)NH—(2S)-2-CH₂OCH₃-pyrrolidin- (Z)-CH-4-F-phenyl 1-yl 1262,4-Cl₂-phenyl C(O)NH—(2R)-2-CH₂OCH₃-pyrrolidin- (Z)-CH-4-F-phenyl 1-yl128 2,4-Cl₂-phenyl C(O)NH—CH(phenyl)-R—CH₃ H

An example of the invention is a compound of Formula (If)

wherein X₂R₂, X₃R₃, and X₄R₄ are dependently selected from Cpd X₂R₂ X₃R₃X₄R₄ 4 CH₂-phenyl CH═CHSO₂NH—CH(phenyl)-R—CH₃ H 10 CH₂-phenylCH═CHSO₂NH—CH(phenyl)-S—CH₃ H 16 CH₂-phenylCH═CHSO₂NH—CH(cyclohexyl)-R—CH₃ H 17 CH₂-phenylCH═CHSO₂NH—CH(cyclohexyl)-S—CH₃ H 82 2,4-Cl₂-phenylC(O)NH—CH(phenyl)-R—CH₃ (Z)-CH-4-F-phenyl 83 2,4-Cl₂-phenylC(O)NH-piperidin-1-yl (Z)-CH-4-F-phenyl 84 2,4-Cl₂-phenylC(O)NH—CH(cyclohexyl)-R—CH₃ (Z)-CH-4-F-phenyl 85 2,4-Cl₂-phenylC(O)NH—CH(cyclohexyl)-S—CH₃ (Z)-CH-4-F-phenyl 86 2,4-Cl₂-phenylC(O)NH—CH(phenyl)-S—CH₃ (Z)-CH-4-F-phenyl 87 2,4-Cl₂-phenylC(O)NH-hexahydro- (Z)-CH-4-F-phenyl cyclopenta[c]pyrrol-2-yl

Compounds of the invention are also represented as follows:

Selected compounds of the invention include:

The present invention is directed to a method for treating, amelioratingor preventing a CB receptor mediated syndrome, disorder or disease in asubject in need thereof comprising the step of administering to thesubject an effective amount of a compound of Formula (I) or prodrug,metabolite, or composition thereof.

The present invention is directed to a method for treating, amelioratingor preventing a CB receptor mediated syndrome, disorder or disease in asubject in need thereof comprising the step of administering to thesubject an effective amount of a compound of Formulae (Ia)-(If) orprodrug, metabolite, or composition thereof.

The present invention is directed to a method for treating, amelioratingor preventing a CB receptor mediated syndrome, disorder or disease in asubject in need thereof comprising the step of administering to thesubject a combination product and/or therapy comprising an effectiveamount of a compound of Formulae (I)-(If) and a therapeutic agent.

Therapeutic agents contemplated for use in a combination product and/ortherapy of the present invention include an anticonvulsant (such astopiramate, analogs of topiramate, carbamazepine, valproic acid,lamotrigine, gabapentin, phenytoin and the like and mixtures orpharmaceutically acceptable salts thereof) or a contraceptive agent(such as progestin-only contraceptives and contraceptives that includeboth a progestin component and an estrogen component).

The invention further includes a pharmaceutical composition wherein thecontraceptive is an oral contraceptive, and wherein the contraceptiveoptionally includes a folic acid component.

The invention also includes a method of contraception in a subjectcomprising administering to the subject a composition, wherein thecomposition comprises a contraceptive and a CB1 receptor inverse-agonistor antagonist compound of Formulae (I)-(If), and wherein the compositionreduces the urge to smoke in the subject and/or assists the subject inlosing weight.

The present invention is also directed to a method for treating,ameliorating or preventing a CB receptor mediated syndrome, disorder ordisease in a subject in need thereof wherein the syndrome, disorder ordisease is related to appetite, metabolism, diabetes,glaucoma-associated intraocular pressure, social and mood disorders,seizures, substance abuse, learning, cognition or memory, organcontraction or muscle spasm, bowel disorders, respiratory disorders,locomotor activity or movement disorders, immune and inflammationdisorders, unregulated cell growth, pain management, neuroprotection andthe like.

Chemistry Definitions and Pharmaceutical Forms

When any variable (e.g., aryl, heterocyclyl, R₁, R₂, etc.) occurs morethan once in a substituent list, its definition on each occurrence isindependent of any other occurrence.

Bond lines drawn into a ring system from a substituent variable (such asR₆, R₁₆, etc.) indicate that the substituent may be attached to any ofthe substitutable ring atoms. If the ring system is polycyclic, thesubstituent may be attached to any of the suitable atoms on the ringinto which the bond line is drawn.

As used herein, the following terms are intended to have the followingdefinitions.

“Alkyl” means a saturated aliphatic branched or straight-chainmonovalent hydrocarbon radical substituent or alkyldiyl linking grouphaving a specified number of carbon atoms, wherein the alkyl radicalsubstituent is derived by the removal of one hydrogen atom from a carbonatom and the alkyldiyl linking group is derived by the removal of onehydrogen atom from each of two carbon atoms in the chain. The term “C₁₋₈alkyl” means a radical having from 1-8 carbon atoms in a linear orbranched arrangement. “C₁₋₆ alkyl” includes methyl, ethyl, propyl,butyl, pentyl, and hexyl. Alkyl and alkyldiyl radicals may be attachedto a core molecule via a terminal carbon atom or via a carbon atomwithin the chain. Similarly, substituent variables may be attached to analkyl or alkyldiyl radical when allowed by available valences.

“Alkoxy” means an alkyl radical attached through an oxygen linking atom.“C₁₋₄ alkoxy” includes the radicals methoxy, ethoxy, propoxy, andbutoxy. An alkoxy radical may be attached to a core molecule and furthersubstituted where indicated.

“Cycloalkyl” means a monovalent saturated or partially unsaturatedcyclic ring system radical. Cycloalkyl ring systems include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,adamantanyl and the like.

“Aryl” means an monovalent aromatic cyclic ring system radical. Arylring systems include phenyl, naphthalenyl, fluorenyl, indenyl, azulenyl,anthracenyl and the like.

“Hetero,” when used as a prefix for a ring system, refers to thereplacement of at least one carbon atom member in the ring system with aheteroatom selected from N, S, O, or P. A hetero ring may have 1, 2, 3,or 4 carbon atom members replaced by a nitrogen atom. Alternatively, aring may have 0, 1, 2, or 3 nitrogen atom members and 1 oxygen or sulfuratom member. Alternatively, up to two adjacent ring members may beheteroatoms; wherein 1 heteroatom is nitrogen and the other heteroatomis selected from N, S, or O.

“Heterocyclyl” means a “hetero” ring system radical having a cycloalkylring as the core molecule. Heterocyclyl ring systems include 2H-pyrrole,2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, 2-imidazolinyl(also referred to as 4,5-dihydro-1H-imidazolyl), imidazolidinyl,2-pyrazolinyl, pyrazolidinyl, tetrazolyl, tetrazolidinyl, piperidinyl,1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyl,azetidinyl, azepanyl, hexahydro-1,4diazepinyl, hexahydro-1,4-oxazepanyl,tetrahydro-furanyl, tetrahydro-thienyl, tetrahydro-pyranyl,tetrahydro-pyridazinyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyland the like.

“Heteroaryl” means a monovalent heteroaromatic ring system radical.Heteroaryl ring systems include furyl, thienyl, pyrrolyl, oxazolyl,thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,indolizinyl, indolyl, azaindolyl, isoindolyl, benzo[b]furyl,benzo[b]thienyl, indazolyl, azaindazolyl, benzimidazolyl, benzthiazolyl,benzoxazolyl, benzisoxazolyl, benzothiadiazolyl, benzotriazolyl,purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl,phthalzinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyland the like.

The term “benzo-fused” refers to a bicyclic fused ring system radicalformed by a monocyclic radical fused with a benzene ring; thebenzo-fused radical may be attached to a core molecule via either ringof the bicyclic system.

The term “benzo-fused cycloalkyl” refers to a bicyclic fused ring systemradical wherein a cycloalkyl ring is fused with a benzene ring.Benzo-fused cycloalkyl ring systems include indanyl,1,2,3,4-tetrahydro-naphthalenyl, 5,6,7,8-tetrahydro-naphthalenyl,6,7,8,9,-tetrahydro-5H-benzocycloheptenyl,5,6,7,8,9,10-hexahydro-benzocyclooctenyl and the like.

“Substituted” refers to a molecule in which one or more hydrogen atomshave been replaced with one or more substituent variables up to thatamount allowed by the available valences.

“Dependently selected” refers to one or more substituent variables thatare specified in an indicated combination for substitution in a coremolecule (e.g., variables that refer to groups of substituents appearingin a tabular list of compounds).

In general, IUPAC nomenclature rules are used herein.

Certain compounds of Formula (I) may exist in various stereoisomeric ortautomeric forms. The invention encompasses all such CB receptormodulating compounds, including active compounds in the form ofessentially pure enantiomers, racemic mixtures, and tautomers.

The compounds of the invention may be present in the form ofpharmaceutically acceptable salts. For use in medicines, the salts ofthe compounds of this invention refer to non-toxic “pharmaceuticallyacceptable salts.” FDA-approved pharmaceutically acceptable salt formsinclude pharmaceutically acceptable acidic/anionic or basic/cationicsalts.

Pharmaceutically acceptable acidic/anionic salts include the acetate,benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calciumedetate, camsylate, carbonate, chloride, citrate, dihydrochloride,edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate,lactate, lactobionate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,pamoate, pantothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate,teoclate, tosylate, and triethiodide salts.

The compounds of the invention include pharmaceutically acceptableanionic salt forms, wherein the anionic salts include the acetate,benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calciumedetate, camsylate, carbonate, chloride, citrate, dihydrochloride,edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate,lactate, lactobionate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,pamoate, pantothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate,teoclate, tosylate, and triethiodide salts.

The anionic salt form of a compound of the invention includes an anionicsalt selected from the acetate, bromide, camsylate, chloride, edisylate,fumarate, hydrobromide, hydrochloride, iodide, isethionate, lactate,mesylate, napsylate, salicylate, sulfate, and tosylate salts.

During any of the processes for preparation of the compounds of theinvention, it may be necessary and/or desirable to protect sensitive orreactive groups on any of the molecules concerned. This may be achievedby means of conventional protecting groups, such as those described inProtective Groups in Organic Chemistry, ed. J. F. W. McOmie, PlenumPress, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups inOrganic Synthesis, 3^(rd) Edition, John Wiley & Sons, 1999. Theprotecting groups may be removed at a convenient subsequent stage usingmethods known in the art.

The invention includes compounds of various isomers and mixturesthereof. The term “isomer” refers to compounds that have the samecomposition and molecular weight but differ in physical and/or chemicalproperties. Such substances have the same number and kind of atoms butdiffer in structure. The structural difference may be in constitution(geometric isomers) or in an ability to rotate the plane of polarizedlight (stereoisomers).

The term “stereoisomer” means isomers of identical constitution thatdiffer in the spatial arrangement of their atoms. Enantiomers anddiastereomers are stereoisomers wherein an asymmetrically substitutedcarbon atom acts as a chiral center. The term “chiral” means a moleculethat is not superimposable on its mirror image, implying the absence ofan axis and a plane or center of symmetry. The term “enantiomer” meansone of a pair of molecular species that are mirror images of each otherand are not superimposable. The term “diastereomer” means stereoisomersthat are not related as mirror images. The symbol “*” in a structuralformula represents the presence of a chiral carbon center. The symbols“R” and “S” represent the configuration of substituents around a chiralcarbon atom(s). The symbols “R*” and “Se” denote the relativeconfigurations of substituents around a chiral carbon atom(s).

The term “racemate” or “racemic mixture” means a compound of equimolarquantities of two enantiomeric species, wherein the compound is devoidof optical activity. The term “optical activity” means the degree towhich a chiral molecule or non-racemic mixture of chiral moleculesrotates the plane of polarized light.

“Geometric isomer” means isomers that differ in the orientation ofsubstituent atoms in relationship to a carbon-carbon double bond, to acycloalkyl ring, or to a bridged bicyclic system. Substituent atoms(other than H) on each side of a carbon-carbon double bond may be in anE or Z configuration. In the “E” configuration, the substituents are onopposite sides in relationship to the carbon-carbon double bond. In the“Z” configuration, the substituents are oriented on the same side inrelationship to the carbon-carbon double bond.

The isomeric descriptors (“R,” “S.” “S*,” “R*,” “E,” and “Z”) indicateatom configurations relative to a core molecule and are intended to beused as defined in the literature.

The compounds of the invention may be prepared as individual isomers byeither isomer-specific synthesis or resolved from an isomeric mixture.Conventional resolution techniques include combining the free base (orfree acid) of each isomer of an isomeric pair using an optically activeacid (or base) to form an optically active salt (followed by fractionalcrystallization and regeneration of the free base), forming an ester oramide of each of the isomers of an isomeric pair by reaction with anappropriate chiral auxiliary (followed by fractional crystallization orchromatographic separation and removal of the chiral auxiliary), orseparating an isomeric mixture of either an intermediate or a finalproduct using various well known chromatographic methods.

Furthermore, compounds of the invention may have one or more polymorphor amorphous crystalline forms. Said forms are included in the scope ofthe invention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents. Said solvates areencompassed within the scope of this invention.

Therapeutic Use

The compounds of the present invention are useful in a method fortreating, ameliorating or preventing a CB mediated syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a compound ofFormula (I).

CB receptors belong to the G-protein-coupled receptor (GCPR) family, areceptor super-family with a distinctive pattern of seven transmembranedomains, which inhibits N-type calcium channels and/or adenylate cyclaseto inhibit Q-type calcium channels.

CB1 receptors are present in the CNS, predominately expressed in brainregions associated with memory and movement such as the hippocampus(memory storage), cerebellum (coordination of motor function, postureand balance), basal ganglia (movement control), hypothalamus (thermalregulation, neuroendocrine release, appetite), spinal cord(nociception), cerebral cortex (emesis) and periphery regions such aslymphoid organs (cell mediated and innate immunity), vascular smoothmuscle cells (blood pressure), gastrointestinal tract (duodenum, ileumand myenteric plexus for emesis control), lung smooth muscle cells(bronchodilation), eye ciliary body (intraocular pressure).

CB2 receptors appear to be primarily expressed peripherally in lymphoidtissue (cell mediated and innate immunity), peripheral nerve terminals(peripheral nervous system), spleen immune cells (immune systemmodulation) and retina (intraocular pressure) and in the CNS incerebellar granule cell mRNA (coordination of motor function).Pharmacological and physiological evidence also suggests that there maybe other CB receptor subtypes that have yet to be cloned andcharacterized.

There are potential areas of clinical application where activation orinhibition of a CB receptor appears to mediate various syndromes,disorders or diseases. Thus, CB receptor modulators, including thecompounds of Formula (I), are useful for treating, ameliorating orpreventing a CB receptor mediated syndrome, disorder or diseaseincluding, but not limited to, controlling or regulating appetite,metabolism, obesity, diabetes, glaucoma-associated intraocular pressure,social and mood disorders, seizure-related disorders, substance abusedisorders, learning, cognition and/or memory disorders, bowel disorders,respiratory disorders, locomotor activity disorders, movement disorders,immune disorders, inflammation disorders, gastrointestinal disorders,organ contraction, muscle spasm, cell growth, pain or management thereofor for use as a neuroprotective agent and the like.

The present invention includes CB receptor modulators useful fortreating, ameliorating or preventing a CB receptor mediated syndrome,disorder or disease. The usefulness of a compound of Formula (I) as a CBreceptor modulator can be determined according to the methods disclosedherein. The scope of such use includes treating, ameliorating orpreventing a plurality of CB receptor mediated syndromes, disorders ordiseases.

A compound of Formulae (I)-(If) for use as a CB receptor modulatorincludes a compound having a mean inhibition constant (IC₅₀) for CBbinding of between about 5 μM to about 0.01 nM; between about 1 μM toabout 0.01 nM; between about 800 nM to about 0.01 nM; between about 200nM to about 0.01 nM; between about 100 nM to about 0.01 nM; betweenabout 80 nM to about 0.01 nM; between about 20 nM to about 0.01 nM;between about 10 nM to about 0.1 nM; or about 1 nM.

A compound of Formulae (I)-(If) for use as a CB receptor modulator ofthe invention includes a compound having a CB1 agonist IC₅₀ for CB1agonist activity of between about 5 μM to about 0.01 nM; between about 1μM to about 0.01 nM; between about 800 nM to about 0.01 nM; betweenabout 200 nM to about 0.01 nM; between about 100 nM to about 0.01 nM;between about 80 nM to about 0.01 nM; between about 20 nM to about 0.01nM; between about 10 nM to about 0.1 nM; or about 1 nM.

A compound of Formulae (I)-(If) for use as a CB receptor modulator ofthe invention includes a compound having a CB1 antagonist IC₅₀ for CB1antagonist activity of between about 5 μM to about 0.01 nM; betweenabout 1 μM to about 0.01 nM; between about 800 nM to about 0.01 nM;between about 200 nM to about 0.01 nM; between about 100 nM to about0.01 nM; between about 80 nM to about 0.01 nM; between about 20 nM toabout 0.01 nM; between about 10 nM to about 0.1 nM; or about 1 nM.

A compound of Formulae (I)-(If) for use as a CB receptor modulator ofthe invention includes a compound having a CB1 inverse-agonist IC₅₀ forCB1 inverse-agonist activity of between about 5 μM to about 0.01 nM;between about 1 μM to about 0.01 nM; between about 800 nM to about 0.01nM; between about 200 nM to about 0.01 nM; between about 100 nM to about0.01 nM; between about 80 nM to about 0.01 nM; between about 20 nM toabout 0.01 nM; between about 10 nM to about 0.1 nM; or about 1 nM.

A compound of Formulae (I)-(If) for use as a CB receptor modulator ofthe invention includes a compound having a CB2 agonist IC₅₀ for CB2agonist activity of between about 5 μM to about 0.01 nM; between about 1μM to about 0.01 nM; between about 800 nM to about 0.01 nM; betweenabout 200 nM to about 0.01 nM; between about 100 nM to about 0.01 nM;between about 80 nM to about 0.01 nM; between about 20 nM to about 0.01nM; between about 10 nM to about 0.1 nM; or about 1 nM.

A compound of Formulae (I)-(If) for use as a CB receptor modulator ofthe invention includes a compound having a CB2 antagonist IC₅₀ for CB2antagonist activity of between about 5 μM to about 0.01 nM; betweenabout 1 μM to about 0.01 nM; between about 800 nM to about 0.01 nM;between about 200 nM to about 0.01 nM; between about 100 nM to about0.01 nM; between about 80 nM to about 0.01 nM; between about 20 nM toabout 0.01 nM; between about 10 nM to about 0.1 nM; or about 1 nM.

A compound of Formulae (I)-(If) for use as a CB receptor modulator ofthe invention includes a compound having a CB2 inverse-agonist IC₅₀ forCB2 inverse-agonist activity of between about 5 μM to about 0.01 nM;between about 1 VM to about 0.01 nM; between about 800 nM to about 0.01nM; between about 200 nM to about 0.01 nM; between about 100 nM to about0.01 nM; between about 80 nM to about 0.01 nM; between about 20 nM toabout 0.01 nM; between about 10 nM to about 0.01 nM; or about 1 nM.

The present invention is further directed to a method for treating,ameliorating or preventing a CB receptor mediated syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a compound ofFormula (I).

The present invention is also directed to a method for treating,ameliorating or preventing a CB receptor mediated syndrome, disorder ordisease in a subject in need thereof wherein the syndrome, disorder ordisease is related to an appetite, metabolism, obesity, diabetes,glaucoma-associated intraocular pressure, social, mood, seizure,substance abuse, learning, cognition, memory, gastrointestinal, organcontraction, muscle spasm, respiratory, locomotor activity, movement,immune, inflammation or an unregulated cell growth or syndrome, disorderor disease or for use in pain management or as a neuroprotection agentfor treating, ameliorating or preventing a CB receptor mediatedsyndrome, disorder or disease.

The present invention is further directed to a method for treating,ameliorating or preventing a CB receptor mediated syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a compound ofFormula (I).

“CB receptor” means any one of the known or heretofore unknown subtypesof the class of CB receptors that may be bound by a compound of thepresent invention, such as the CB1 or CB2 receptor. The term “modulator”further refers to the use of a compound of the invention as a CBreceptor agonist, antagonist or inverse-agonist.

“Subject” means a patient, which may be an animal, preferably a mammal,most preferably a human, who has a disease or disorder or is at risk of(or susceptible to) developing a CB receptor mediated syndrome, disorderor disease.

“Administering,” with respect to the methods of the invention, means amethod for treating, ameliorating or preventing a syndrome, disorder ordisease as described herein with a compound of the invention or prodrug,metabolite or composition thereof. Such methods include administering aneffective amount thereof at different times during the course of atherapy or concurrently in a combination form. Prophylacticadministration can occur prior to the manifestation of symptomscharacteristic of a CB receptor mediated syndrome, disorder or diseasesuch that the syndrome, disorder or -disease is prevented or otherwisedelayed in its development. Therapeutic administration occurs oncesymptoms characteristic of a CB receptor mediated syndrome, disorder ordisease have manifested such that the syndrome, disorder or disease istreated, ameliorated or otherwise delayed in its progression. Themethods of the invention are to be understood as embracing all knowntherapeutic treatment regimens.

“Prodrug” means a pharmaceutically acceptable form of a functionalderivative of a compound of the invention (or a salt thereof), whereinthe prodrug may be: 1) a relatively active precursor which converts invivo to an active prodrug component; 2) a relatively inactive precursorwhich converts in vivo to an active prodrug component; or 3) arelatively less active component of the compound that contributes totherapeutic biological activity after becoming available in vivo (i.e.,as a metabolite). Conventional procedures for the selection andpreparation of suitable prodrug derivatives are described, for example,in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

“Metabolite” means a pharmaceutically acceptable form of a metabolicderivative of a compound of the invention (or a salt thereof), whereinthe derivative is a relatively less active component of the compoundthat contributes to therapeutic biological activity after becomingavailable in vivo.

“Effective amount” means that amount of a compound of Formula (I) thatis effective in an animal or human to treat, ameliorate or prevent thesymptoms of the CB receptor mediated syndrome, disorder or disease beingtreated. The effective amount of a compound of the invention is fromabout 0.001 mg/kg/day to about 300 mg/kg/day.

“CB receptor mediated syndrome, disorder or disease” refers tosyndromes, disorders or diseases associated with a biological responsemediated by a CB receptor such that there is discomfort or decreasedlife expectancy to the organism.

CB receptor mediated syndromes, disorders or diseases can occur in bothanimals and humans and include a syndrome, disorder or disease relatedto an appetite, metabolism, obesity, diabetes, glaucoma-associatedintraocular pressure, social, mood, seizure, substance abuse, learning,cognition, memory, gastrointestinal, organ contraction, muscle spasm,respiratory, locomotor activity, movement, immune, inflammation, cellgrowth, pain or neurodegenerative syndrome, disorder or disease.

Appetite related syndromes, disorders or diseases include obesity,overweight condition, anorexia, bulimia, cachexia, dysregulated appetiteand the like.

Metabolism related syndromes, disorders or diseases include metabolicsyndrome, dyslipidemia, elevated blood pressure, diabetes, insulinsensitivity or resistance, hyperinsulinemia, hypercholesterolemia,hyperlipidemias, hypertriglyceridemias, atherosclerosis, hepatomegaly,steatosis, abnormal alanine aminotransferase levels, inflammation,atherosclerosis and the like.

Obesity related syndromes, disorders or diseases include obesity as aresult of genetics, diet, food intake volume, metabolic syndrome,disorder or disease, hypothalmic disorder or disease, age, reducedactivity, abnormal adipose mass distribution, abnormal adiposecompartment distribution and the like.

Diabetes related syndromes, disorders or diseases include glucosedysregulation, insulin resistance, glucose intolerance,hyperinsulinemia, dyslipidemia, hypertension, obesity and the like.

Type II diabetes mellitus (non-insulin-dependent diabetes mellitus) is ametabolic disorder (i.e., a metabolism related syndrome, disorder ordisease) in which glucose dysregulation and insulin resistance resultsin chronic, long-term medical complications for both adolescents andadults affecting the eyes, kidneys, nerves and blood vessels and canlead to blindness, end-stage renal disease, myocardial infarction orlimb amputation and the like. Glucose dysregulation includes theinability to make sufficient insulin (abnormal insulin secretion) andthe inability to effectively use insulin (resistance to insulin actionin target organs and tissues). Individuals suffering from Type IIdiabetes mellitus have a relative insulin deficiency. That is, in suchindividuals, plasma insulin levels are normal to high in absolute terms,although they are lower than predicted for the level of plasma glucosethat is present.

Type II diabetes mellitus is characterized by the following clinicalsigns or symptoms: persistently elevated plasma glucose concentration orhyperglycemia; polyuria; polydipsia and/or polyphagia; chronicmicrovascular complications such as retinopathy, nephropathy andneuropathy; and macrovascular complications such as hyperlipidemia andhypertension. These micro-and macro-vascular complications can lead toblindness, end-stage renal disease, limb amputation and myocardialinfarction.

Insulin Resistance Syndrome (IRS) (also referred to as Syndrome X,Metabolic Syndrome or Metabolic Syndrome X) is a disorder that presentsrisk factors for the development of Type II diabetes and cardiovasculardisease including glucose intolerance, hyperinsulinemia, insulinresistance, dyslipidemia (e.g. high triglycerides, low HDL-cholesteroland the like), hypertension and obesity.

Social or mood related syndromes, disorders or diseases includedepression, anxiety, psychosis, social affective disorders or cognitivedisorders and the like.

Substance abuse related syndromes, disorders or diseases include drugabuse, drug withdrawal, alcohol abuse, alcohol withdrawal, nicotinewithdrawal, cocaine abuse, cocaine withdrawal, heroin abuse, heroinwithdrawal and the like.

Learning, cognition or memory related syndromes, disorders or diseasesinclude memory loss or impairment as a result of age, disease, sideeffects of medications (adverse events) and the like.

Muscle spasm syndromes, disorders or diseases include multiplesclerosis, cerebral palsy and the like.

Locomotor activity and movement syndromes, disorders or diseases includestroke, Parkinson's disease, multiple sclerosis, epilepsy and the like.

Bowel related syndromes, disorders or diseases include bowel dysmotilityassociated disorders (either accompanied by pain, diarrhea orconstipation or without), irritable bowel syndrome (and other forms ofbowel dysmotility and the like), inflammatory bowel diseases (such asulcerative colitis, Crohn's disease and the like) and celiac disease.

Respiratory related syndromes, disorders or diseases include chronicpulmonary obstructive disorder, emphysema, asthma, bronchitis and thelike.

Immune or inflammation related syndromes, disorders or diseases includeallergy, rheumatoid arthritis, dermatitis, autoimmune disease,immunodeficiency, chronic neuropathic pain and the like.

Cell growth related syndromes, disorders or diseases includedysregulated mammalian cell proliferation, breast cancer cellproliferation, prostrate cancer cell proliferation and the like.

Pain related syndromes, disorders or diseases include central andperipheral pathway mediated pain, bone and joint pain, migraine headacheassociated pain, cancer pain, menstrual cramps, labor pain and the like.

Neurodegenerative related syndromes, disorders or diseases includeParkinson's Disease, multiple sclerosis, epilepsy, ischemia or secondarybiochemical injury collateral to traumatic head or brain injury, braininflammation, eye injury or stroke and the like.

An example of the invention includes a method for treating, amelioratingor preventing a CB receptor mediated metabolism related syndrome,disorder or disease, an appetite related syndrome, disorder or disease,a diabetes related syndrome, disorder or disease, an obesity relatedsyndrome, disorder or disease or a learning, cognition or memory relatedsyndrome, disorder or disease in a subject in need thereof comprisingadministering to the subject an effective amount of a compound of thepresent invention or composition thereof.

An example of the invention includes a method for treating, amelioratingor preventing a CB receptor agonist mediated syndrome, disorder ordisease in a subject in need thereof comprising administering to thesubject an effective amount of a compound of Formula (I).

An example of the invention includes a method for treating, amelioratingor preventing a CB receptor inverse-agonist mediated syndrome, disorderor disease in a subject in need thereof comprising administering to thesubject an effective amount of a compound of Formula (I).

An example of the invention includes a method for treating, amelioratingor preventing a CB receptor antagonist mediated syndrome, disorder ordisease in a subject in need thereof comprising administering to thesubject an effective amount of a compound of Formula (I).

An example of the invention includes a method for treating, amelioratingor preventing a CB1 receptor agonist mediated syndrome, disorder ordisease in a subject in need thereof comprising administering to thesubject an effective amount of a compound of Formula (I).

An example of the invention includes a method for treating, amelioratingor preventing a CB1 receptor antagonist mediated syndrome, disorder ordisease in a subject in need thereof comprising administering to thesubject an effective amount of a compound of Formula (I).

An example of the invention includes a method for treating, amelioratingor preventing a CB1 receptor inverse-agonist mediated syndrome, disorderor disease in a subject in need thereof comprising administering to thesubject an effective amount of a compound of Formula (I).

An example of the invention includes a method for treating, amelioratingor preventing a CB1 receptor inverse-agonist mediated appetite relatedsyndrome, disorder or disease in a subject in need thereof, comprisingadministering to the subject an effective amount of a compound ofFormula (I), wherein appetite related syndromes, disorders or diseasesinclude obesity, overweight condition, anorexia, bulimia, cachexia,dysregulated appetite and the like.

An example of the invention includes a method for treating, amelioratingor preventing a CB1 receptor inverse-agonist mediated obesity relatedsyndrome, disorder or disease in a subject in need thereof, comprisingadministering to the subject an effective amount of a compound ofFormula (I), wherein obesity related syndromes, disorders or diseasesinclude obesity as a result of genetics, diet, food intake volume,metabolic syndrome, disorder or disease, hypothalmic disorder ordisease, age, reduced activity, abnormal adipose mass distribution,abnormal adipose compartment distribution and the like.

An example of the invention includes a method for treating, amelioratingor preventing a CB1 receptor inverse-agonist mediated metabolism relatedsyndrome, disorder or disease in a subject in need thereof, comprisingadministering to the subject an effective amount of a compound ofFormula (I), wherein metabolism related syndromes, disorders or diseasesinclude metabolic syndrome, dyslipidemia, elevated blood pressure,diabetes, insulin sensitivity or resistance, hyperinsulinemia,hypercholesterolemia, hyperlipidemias, hypertriglyceridemias,atherosclerosis, hepatomegaly, steatosis, abnormal alanineaminotransferase levels, inflammation, atherosclerosis and the like.

An example of the invention includes a method for treating, amelioratingor preventing a CB2 receptor agonist mediated syndrome, disorder ordisease in a subject in need thereof comprising administering to thesubject an effective amount of a compound of Formula (I).

An example of the invention includes a method for treating, amelioratingor preventing a CB2 receptor antagonist mediated syndrome, disorder ordisease in a subject in need thereof comprising administering to thesubject an effective amount of a compound of Formula (I).

An example of the invention includes a method for treating, amelioratingor preventing a CB2 receptor inverse-agonist mediated syndrome, disorderor disease in a subject in need thereof comprising administering to thesubject an effective amount of a compound of Formula (I).

The present invention further includes a method for use of an instantcompound in a combination product and/or therapy for treating,ameliorating or preventing a CB receptor mediated syndrome, disorder ordisease related to an appetite, metabolism, obesity, diabetes,glaucoma-associated intraocular pressure, social, mood, seizure,substance abuse, learning, cognition, memory, gastrointestinal, organcontraction, muscle spasm, respiratory, locomotor activity, movement,immune, inflammation, cell growth, pain or neurodegenerative syndrome,disorder or disease in a subject in need thereof comprisingadministering to the subject an effective amount of the combinationproduct, wherein the product is one or more of a compound of Formulae(I)-(If) combined with one or more therapeutic agents.

Unless specified otherwise, “combination product and/or therapy” means apharmaceutical composition comprising a compound of Formulae (I)-(If) incombination with one or more therapeutic agents. As those skilled in theart will appreciate, the dosages of the compound and the one or moretherapeutic agents are adjusted when combined to achieve an effectiveamount. The effective amounts of the compound and agent may beindependently optimized and combined to achieve a synergistic resultwhereby the pathology is reduced more than it would be if either thecompound or agent were used alone.

With respect to the method for use of a combination product and/ortherapy for treating, ameliorating or preventing a CB receptor mediatedsyndrome, disorder or disease, the term “effective amount” means thatamount of the compound and agent taken together so that the combinedeffect treats, ameliorates or prevents the symptoms of the syndrome,disorder or disease.

With respect to the method for use of a combination product and/ortherapy, the term “administering,” is also intended to includeco-administering an effective amount of the compound and the agent,sequential administration of the compound and the agent, administrationof a single composition containing of the compound and the agent orsimultaneous administration of separate, divided compositions containingthe compound and the agent. The methods of the invention are thereforefurther to be understood as embracing all such regimes of simultaneousor alternating treatment regimens.

Therapeutic agents contemplated for use in a combination product and/ortherapies of the present invention include anticonvulsants orcontraceptive agents or composition(s) thereof. It should be understoodthat contraceptive agents suitable for use in a combination productand/or therapy are not limited to oral contraceptives, but also includeother commonly available contraceptives such as those that areadministered transdermally, by injection or via implant.

For example, the effective amount of a combination product and/ortherapy comprising administration of a compound of Formula (I) and ananticonvulsant would be the amount of the compound of Formula (I) andthe amount of the anticonvulsant that when taken together orsequentially have a combined effect that is therapeutically orprophylactically effective.

Further, it will be recognized by one skilled in the art that in thecase of combination product and/or therapy with a therapeutically orprophylactically effective amount, as in the example above, the amountof the compound of Formula (I) and/or the amount of the anticonvulsantindividually may or may not be effective.

Wherein the present invention is directed to the administration of acombination product and/or therapy, the instant compound and theanticonvulsant or contraceptive agent may be co-administered by anysuitable means, simultaneously, sequentially or in a singlepharmaceutical composition.

Where the instant compound(s) and the anticonvulsant or contraceptiveagent components are administered separately, the number of dosages ofeach compound(s) given per day, may not necessarily be the same, e.g.where one compound may have a greater duration of activity, and willtherefore, be administered less frequently.

The compound(s) and the anticonvulsant(s) or contraceptive agent(s) ofthe combination product and/or therapy may be administered via the sameor different routes of administration.

An example of the invention includes a method for treating, amelioratingor preventing a CB receptor mediated syndrome, disorder or disease in asubject in need thereof comprising administering to the subject aneffective amount of a combination product and/or therapy, wherein theproduct and/or therapy is one or more of a compound of Formula (I)combined with one or more anticonvulsants.

An example of the invention includes a method for treating, amelioratingor preventing a CB receptor agonist mediated syndrome, disorder ordisease in a subject in need thereof comprising administering to thesubject an effective amount of a combination product and/or therapy,wherein the product and/or therapy is one or more of a compound ofFormula (I) combined with one or more anticonvulsants.

An example of the invention includes a method for treating, amelioratingor preventing a CB receptor antagonist mediated syndrome, disorder ordisease in a subject in need thereof comprising administering to thesubject an effective amount of a combination product and/or therapy,wherein the product and/or therapy is one or more of a compound ofFormula (I) combined with one or more anticonvulsants.

An example of the invention includes a method for treating, amelioratingor preventing a CB receptor inverse-agonist mediated syndrome, disorderor disease in a subject in need thereof comprising administering to thesubject an effective amount of a combination product and/or therapy,wherein the product and/or therapy is one or more of a compound ofFormula (I) combined with one or more anticonvulsants.

An example of the invention includes a method for treating, amelioratingor preventing a CB receptor mediated syndrome, disorder or disease in asubject in need thereof comprising administering to the subject aneffective amount of a combination product and/or therapy, wherein theproduct and/or therapy is one or more of a compound of Formula (I)combined with one or more contraceptives.

An example of the invention includes a method for treating, amelioratingor preventing a CB receptor agonist mediated syndrome, disorder ordisease in a subject in need thereof comprising administering to thesubject an effective amount of a combination product and/or therapy,wherein the product and/or therapy is one or more of a compound ofFormula (I) combined with one or more contraceptives.

An example of the invention includes a method for treating, amelioratingor preventing a CB receptor antagonist mediated syndrome, disorder ordisease in a subject in need thereof comprising administering to thesubject an effective amount of a combination product and/or therapy,wherein the product and/or therapy is one or more of a compound ofFormula (I) combined with one or more contraceptives.

An example of the invention includes a method for treating, amelioratingor preventing a CB receptor inverse-agonist mediated syndrome, disorderor disease in a subject in need thereof comprising administering to thesubject an effective amount of a combination product and/or therapy,wherein the product and/or therapy is one or more of a compound ofFormula (I) combined with one or more contraceptives.

An example of the invention includes a method for treating, amelioratingor preventing a CB1 receptor agonist mediated syndrome, disorder ordisease in a subject in need thereof comprising administering to thesubject an effective amount of a combination product and/or therapy,wherein the product and/or therapy is one or more of a compound ofFormula (I) combined with one or more anticonvulsants.

An example of the invention includes a method for treating, amelioratingor preventing a CB1 receptor antagonist mediated syndrome, disorder ordisease in a subject in need thereof comprising administering to thesubject an effective amount of a combination product and/or therapy,wherein the product and/or therapy is one or more of a compound ofFormula (I) combined with one or more anticonvulsants.

An example of the invention includes a method for treating, amelioratingor preventing a CB1 receptor inverse-agonist mediated syndrome, disorderor disease in a subject in need thereof comprising administering to thesubject an effective amount of a combination product and/or therapy,wherein the product and/or therapy is one or more of a compound ofFormula (I) combined with one or more anticonvulsants.

An example of the invention includes a method for treating, amelioratingor preventing a CB1 receptor agonist mediated syndrome, disorder ordisease in a subject in need thereof comprising administering to thesubject an effective amount of a combination product and/or therapy,wherein the product and/or therapy is one or more of a compound ofFormula (I) combined with one or more contraceptives.

An example of the invention includes a method for treating, amelioratingor preventing a CB1 receptor antagonist mediated syndrome, disorder ordisease in a subject in need thereof comprising administering to thesubject an effective amount of a combination product and/or therapy,wherein the product and/or therapy is one or more of a compound ofFormula (I) combined with one or more contraceptives.

An example of the invention includes a method for treating, amelioratingor preventing a CB1 receptor inverse-agonist mediated syndrome, disorderor disease in a subject in need thereof comprising administering to thesubject an effective amount of a combination product and/or therapy,wherein the product and/or therapy is one or more of a compound ofFormula (I) combined with one or more contraceptives.

An example of the invention includes a method for treating, amelioratingor preventing a CB1 receptor inverse-agonist mediated appetite relatedsyndrome, disorder or disease in a subject in need thereof comprisingadministering to the subject an effective amount of a combinationproduct and/or therapy, wherein the product and/or therapy is one ormore of a compound of Formula (I) combined with one or moreanticonvulsants.

An example of the invention includes a method for treating, amelioratingor preventing a CB1 receptor inverse-agonist mediated obesity relatedsyndrome, disorder or disease in a subject in need thereof comprisingadministering to the subject an effective amount of a combinationproduct and/or therapy, wherein the product and/or therapy is one ormore of a compound of Formula (I) combined with one or moreanticonvulsants.

Appetite related syndromes, disorders or diseases include obesity,overweight condition, anorexia, bulimia, cachexia, dysregulated appetiteand the like.

Obesity related syndromes, disorders or diseases include obesity as aresult of genetics, diet, food intake volume, metabolic syndrome,disorder or disease, hypothalmic disorder or disease, age, reducedactivity, abnormal adipose mass distribution, abnormal adiposecompartment distribution and the like.

An example of the invention includes a method for treating, amelioratingor preventing a CB1 receptor inverse-agonist mediated metabolism relatedsyndrome, disorder or disease in a subject in need thereof comprisingadministering to the subject a therapeutically or prophylacticallyeffective amount of a compound of the present invention in a combinationproduct and/or therapy with an anticonvulsant or composition thereof.

Metabolism related syndromes, disorders or diseases include metabolicsyndrome, dyslipidemia, elevated blood pressure, diabetes, insulinsensitivity or resistance, hyperinsulinemia, hypercholesterolemia,hyperlipidemias, hypertriglyceridemias, atherosclerosis, hepatomegaly,steatosis, abnormal alanine aminotransferase levels, inflammation,atherosclerosis and the like.

An example of the invention includes a method for treating, amelioratingor preventing a CB2 receptor agonist mediated syndrome, disorder ordisease in a subject in need thereof comprising administering to thesubject a therapeutically or prophylactically effective amount of acompound of the present invention in a combination product and/ortherapy with an anticonvulsant or composition thereof.

An example of the invention includes a method for treating, amelioratingor preventing a CB2 receptor antagonist mediated syndrome, disorder ordisease in a subject in need thereof comprising administering to thesubject a therapeutically or prophylactically effective amount of acompound of the present invention in a combination product and/ortherapy with an anticonvulsant or composition thereof.

An example of the invention includes a method for treating, amelioratingor preventing a CB2 receptor inverse-agonist mediated syndrome, disorderor disease in a subject in need thereof comprising administering to thesubject a therapeutically or prophylactically effective amount of acompound of the present invention in a combination product and/ortherapy with an anticonvulsant or composition thereof.

An example of the invention includes a method for treating, amelioratingor preventing a CB receptor mediated syndrome, disorder or disease in asubject in need thereof comprising administering to the subject aneffective amount of a combination product and/or therapy, wherein theproduct and/or therapy is one or more of a compound of Formula (I)combined with one or more anticonvulsants selected from topiramate,analogs of topiramate, carbamazepine, valproic acid, lamotrigine,gabapentin or phenytoin or pharmaceutically acceptable forms andmixtures thereof.

An example of the invention includes a method for treating, amelioratingor preventing a CB1 receptor mediated syndrome, disorder or disease in asubject in need thereof comprising administering to the subject aneffective amount of a combination product and/or therapy, wherein theproduct and/or therapy is one or more of a compound of Formula (I)combined with one or more anticonvulsants selected from topiramate,analogs of topiramate, carbamazepine, valproic acid, lamotrigine,gabapentin or phenytoin or pharmaceutically acceptable forms andmixtures thereof.

An example of the invention includes a method for treating, amelioratingor preventing a CB2 receptor mediated syndrome, disorder or disease in asubject in need thereof comprising administering to the subject aneffective amount of a combination product and/or therapy, wherein theproduct and/or therapy is one or more of a compound of Formula (I)combined with one or more anticonvulsants selected from topiramate,analogs of topiramate, carbamazepine, valproic acid, lamotrigine,gabapentin or phenytoin or pharmaceutically acceptable forms andmixtures thereof.

“Topiramate” means 2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranosesulfamate, an anticonvulsant globally marketed for the treatment ofseizures in patients with simple and complex partial epilepsy, for thetreatment of seizures in patients with primary or secondary generalizedseizures and for the treatment of a variety of central and peripheralnervous system syndromes, disorders or diseases.

Topiramate is currently available for oral administration in roundtablets containing 25 mg, 100 mg or 200 mg of active agent, and as 15 mgand 25 mg sprinkle capsules for oral administration as whole capsules oropened and sprinkled onto soft food. U.S. Pat. No. 4,513,006,incorporated herein by reference, discloses topiramate and analogs oftopiramate, their manufacture and use for treating epilepsy.Additionally, topiramate may also be made by the process disclosed inU.S. Pat. Nos. 5,242,942 and 5,384,327, which are incorporated byreference herein.

“Analogs of topiramate”, means sulfamate compounds of topiramate whichare disclosed in U.S. Pat. No. 4,513,006 (see, e.g., column 1, lines36-65), incorporated herein by reference.

An effective amount of topiramate (or analog of topiramate) for use in acombination product in a method of the present invention is in a rangeselected from about 10 to about 1000 mg once or twice daily, from about10 to about 650 mg once or twice daily, or from about 15 to about 325 mgonce or twice daily.

“Carbamazepine” means 5H-dibenz[b,f]azepine-5-carboxamide, ananticonvulsant and specific analgesic for trigeminal neuralgia,available for oral administration as chewable tablets of 100 mg, tabletsof 200 mg, XR (extended release) tablets of 100, 200, and 400 mg, and asa suspension of 100 mg/S mL (teaspoon); U.S. Pat. No. 2,948,718, hereinincorporated by reference in its entirety, discloses carbamazepine andits methods of use.

An effective amount of carbamazepine for use in a combination product ina method of the present invention is in a range selected from about 200to about 1200 mg daily, or about 400 mg daily.

“Valproic acid” means 2-propylpentanoic acid or dipropylacetic acid, anantiepileptic agent commercially available as soft elastic capsulescontaining 250 mg valproic acid, and as syrup containing the equivalentof 250 mg valproic acid per 5 mL as the sodium salt. Valproic acid andvarious pharmaceutically acceptable salts are disclosed in U.S. Pat. No.4,699,927, which is incorporated by reference herein in its entirety.

An effective amount of valproic acid for use in a combination product ina method of the present invention is in a range selected from about 250to about 2500 mg once daily, or about 1000 mg once daily.

“Lamotrigine” means 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine,an antiepileptic drug commercially available for oral administration astablets containing 25 mg, 100 mg, 150 mg, and 200 mg of lamotrigine, andas chewable dispersible tablets containing 2 mg, 5 mg, or 25 mg oflamotrigine. Lamotrigine and its uses are disclosed in U.S. Pat. No.4,486,354, incorporated by reference herein in its entirety.

An effective amount of lamotrigine for use in a combination product in amethod of the present invention is in a range selected from about 50 toabout 600 mg once or twice daily, from about 200 to about 400 mg oncedaily, or about 320 mg once daily.

“Gabapentin” means 1-(aminomethyl)cyclohexaneacetic acid, a commerciallyavailable adjunct drug for treatment of epilepsy and postherpeticneuralgia in adults containing 100 mg, 300 mg, and 400 mg of gabapentin,film-coated tablets containing 600 mg and 800 mg of gabapentin, and anoral solution containing 250 mg/5 mL of gabapentin. Gabapentin and itsmethods of use are described in U.S. Pat. Nos. 4,024,175 and 4,087,544,herein incorporated by reference in their entirety.

An effective amount of gabapentin for use in a combination product in amethod of the present invention is in a range selected from about 300 toabout 3600 mg once daily in two to three divided doses, from about 300to about 1800 mg once daily, or about 900 mg once daily.

“Phenytoin sodium” means 5,5-diphenylhydantoin sodium salt, ananticonvulsant commercially available for oral administration ascapsules containing 100 mg, 200 mg or 300 mg of phenytoin sodium.

An effective amount of phenytoin sodium for use in a combination productin a method of the present invention is in a range selected from about100 to about 500 mg once daily, from about 300 to about 400 mg oncedaily, or about 300 mg once daily.

An example of the invention includes a method for treating, amelioratingor preventing a CB receptor mediated syndrome, disorder or disease in asubject in need thereof comprising administering to the subject aneffective amount of a combination product and/or therapy, wherein theproduct and/or therapy is one or more of a compound of Formula (I)combined with one or more contraceptives or pharmaceutically acceptableforms and mixtures thereof.

An example of the invention includes a method for treating, amelioratingor preventing a CB1 receptor mediated syndrome, disorder or disease in asubject in need thereof comprising administering to the subject aneffective amount of a combination product and/or therapy, wherein theproduct and/or therapy is one or more of a compound of Formula (I)combined with one or more contraceptives or pharmaceutically acceptableforms and mixtures thereof.

An example of the invention includes a method for treating, amelioratingor preventing a CB2 receptor mediated syndrome, disorder or disease in asubject in need thereof comprising administering to the subject aneffective amount of a combination product and/or therapy, wherein theproduct and/or therapy is one or more of a compound of Formula (I)combined with one or more contraceptives or pharmaceutically acceptableforms and mixtures thereof.

Contraceptives suitable for use in a combination product and/or therapyinclude, for example, ORTHO CYCLEN®, ORTHO TRI-CYCLEN®, ORTHO TRI-CYCLENLO®, and ORTHO EVRA®, all available from Ortho-McNeil Pharmaceutical,Inc., Raritan, N.J. It should also be understood that contraceptivessuitable for use in the invention encompass those contraceptives thatinclude a folic acid component.

Smoking and/or obesity have been identified as risk factors in womentaking oral contraceptives. CB receptor antagonists and inverse agonistsand, more particularly, CB1 receptor antagonists and inverse agonistshave been found to be useful therapeutic agents for reducing the urge tosmoke and for assisting patients with eating disorders to lose weight.

Accordingly, the invention further includes a method of reducing therisk factors associated with smoking and/or obesity for women takingcontraceptives by co-administering with a contraceptive at least one ofa CB1 receptor antagonist and/or CB1 receptor inverse-agonist compoundof Formulae (I)-(If).

The use of such compounds or a pharmaceutical composition or medicamentthereof is to reduce the desire to smoke and/or to assist in weight lossfor patients taking contraceptives.

Pharmaceutical Compositions

The present invention includes a pharmaceutical composition ormedicament comprising an admixture of a compound of the presentinvention and an optional pharmaceutically acceptable carrier.

The present invention includes a pharmaceutical composition ormedicament comprising an admixture of two or more compounds of thepresent invention and an optional pharmaceutically acceptable carrier.

The present invention also includes a pharmaceutical composition ormedicament comprising an admixture of a compound of Formula (I), atherapeutic agent and an optional pharmaceutically acceptable carrier.

Such pharmaceutical compositions are particularly useful for treating asubject suffering from a metabolism related syndrome, disorder ordisease, an appetite related syndrome, disorder or disease, a diabetesrelated syndrome, disorder or disease, an obesity related syndrome,disorder or disease, or a learning, cognition or memory relatedsyndrome, disorder or disease.

Pharmaceutical compositions of the invention may, alternatively or inaddition to a compound of Formula (I), comprise a pharmaceuticallyacceptable salt of a compound of Formula (I) or a prodrug orpharmaceutically active metabolite of such a compound or salt inadmixture with a pharmaceutically acceptable carrier.

“Composition” means a product comprising at least a compound of theinvention and a pharmaceutically acceptable carrier or any suchalternatives to a compound of the invention and a pharmaceuticallyacceptable carrier, as well as any product that results, directly orindirectly, from such combinations. The invention further comprisesmixing one or more of the compounds of the invention and apharmaceutically acceptable carrier; and, includes those compositionsresulting from such a process. Contemplated processes include bothtraditional and modern pharmaceutical techniques.

“Medicament” means a product for use in treating, ameliorating orpreventing a CB receptor mediated syndrome, disorder or disease.

“Pharmaceutically acceptable carrier” means molecular entities andcompositions that are of sufficient purity and quality for use in theformulation of a composition of the invention and that, whenappropriately administered to an animal or a human, do not produce anadverse, allergic, or other untoward reaction. Since both human andveterinary uses are included within the scope of the invention, apharmaceutically acceptable formulation includes a composition ormedicament for either human or veterinary use.

The composition may take a wide variety of forms to effectuate mode ofadministration including ocular, oral, sublingual, nasal (inhaled orinsufflated), transdermal, rectal, vaginal, topical (with or withoutocclusion), intravenous (both bolus and infusion), and injection(intraperitoneally, subcutaneously, intramuscularly, intratumorally, orparenterally). Compounds may also be administrated directly to thenervous system including, but not limited to the intracerebral,intraventricular, intracerebroventricular, intrathecal, intracisternal,intraspinal and/or peri-spinal routes of administration by delivery viaintracranial or intravertebral needles and/or catheters with or withoutpump devices.

The composition may be in a dosage unit such as a tablet, pill, capsule,syrup, elixir, emulsion, powder, granule, liposome, ion exchange resin,sterile ocular solution, or ocular delivery device (such as a contactlens and the like facilitating immediate release, timed release, orsustained release), solution or suspension (for parenteral or oral use),metered aerosol or liquid spray, drop, ampoule, auto-injector device, orsuppository; for administration ocularly, orally, intranasally,sublingually, parenterally, or rectally or by inhalation orinsufflation.

Compositions suitable for oral administration include solid forms suchas pills, tablets, caplets, capsules (each including immediate release,timed release, and sustained release formulations), granules andpowders; and, liquid forms such as solutions, syrups, elixirs,emulsions, and suspensions. Forms useful for ocular administrationinclude sterile solutions or ocular delivery devices. Forms useful forparenteral administration include sterile solutions, emulsions andsuspensions.

Alternatively, the composition may be administered in a form suitablefor once-weekly or once-monthly administration. For example, aninsoluble salt of the active compound may be adapted to provide a depotpreparation for intramuscular injection (e.g., a decanoate salt) or toprovide a solution for ophthalmic administration.

The dosage form containing the composition thereof contains an effectiveamount of the compound of the invention necessary to provide atherapeutic or prophylactic effect. The composition may contain fromabout 0.001 mg to about 5000 mg (preferably, from about 0.001 to about500 mg) of a compound of the invention or salt form thereof and may beconstituted into any form suitable for the mode of administrationselected for a subject in need.

A contemplated effective amount may range from about 0.001 mg to about300 mg/kg of body weight per day. Preferably, the range is from about0.003 to about 100 mg/kg of body weight per day. Most preferably, therange is from about 0.005 to about 15 mg/kg of body weight per day. Thecomposition may be administered according to a dosage regimen of fromabout 1 to about 5 times per day.

For oral administration, the composition is preferably in the form of atablet or capsule containing, e.g., 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0,10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, or 500 milligrams of thecompound of the invention for the symptomatic adjustment of the dosageto the patient to be treated. Optimal dosages will vary depending onfactors associated with the particular patient being treated (e.g., age,weight, diet, time of administration, the severity and advancement ofthe condition being treated, the compound being employed, the mode ofadministration, the strength of the preparation and concomitantdiseases. The use of either daily administration or post-periodic dosingmay be employed. An optimal dose to be administered may be readilydetermined by those skilled in the art.

The oral composition is preferably formulated as a homogeneouscomposition wherein the compound of the invention is dispersed evenlythroughout the mixture, which may be readily subdivided into dosageunits containing equal amounts of a compound of the invention.Preferably, the compositions are prepared by mixing a compound of theinvention (or pharmaceutically acceptable salt thereof) with one or morepharmaceutical carriers.

Because of their ease of administration, tablets and capsules representan advantageous oral dosage unit form wherein solid pharmaceuticalcarriers are employed. If desired, tablets may be sugarcoated orfilmcoated using standard techniques. Tablets may also be coated orotherwise compounded to provide a prolonged, control-release therapeuticeffect.

Compounds of the invention may also be administered via a slow releasecomposition, wherein the composition includes a biodegradable slowrelease carrier (e.g., a polymeric carrier) or a pharmaceuticallyacceptable non-biodegradable slow release carrier (e.g., an ion exchangecarrier).

Biodegradable and non-biodegradable slow release carriers are well knownin the art. Biodegradable carriers are used to form particles ormatrices which retain an active agent(s) and which slowlydegrade/dissolve in a suitable environment (e.g., aqueous, acidic, basicand the like) to release the agent.

The compound of Formula (I) may be incorporated for administrationorally or by injection in a liquid form. The compounds may alternativelybe administered parenterally via injection.

Compounds of the invention may be administered intranasally using asuitable intranasal vehicle. Compounds of the invention may beadministered topically using a suitable topical transdermal vehicle or atransdermal patch. Administration via a transdermal delivery systemrequires a continuous rather than intermittent dosage regimen.

A representative compound of Formula (I) or a form thereof for use inthe therapeutic methods and pharmaceutical compositions, medicines ormedicaments described herein includes a compound selected from:

-   1-benzyl-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid [(1R)-1-phenyl-ethyl]-amide,-   (E)-2-(1-benzyl-1,4,6,7-tetrahydro-thiopyrano[4-3-c]pyrazol-3-yl)-ethenesulfonic    acid [(1S)-1-phenyl-ethyl]-amide,-   1-benzyl-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid [(1R)-1-phenyl-ethyl]-amide,-   1-benzyl-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid (1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl)-amide,-   1-benzyl-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid (1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl)-amide,-   1-benzyl-5-oxo-4,5,6,7-tetrahydro-1H-5λ⁴-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid (1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl)-amide,-   (E)-2-[1-(2,4-difluoro-phenyl)-7-(3-fluoro-benzyl)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl]-ethenesulfonic    acid [(1R)-1-cyclohexyl-ethyl]-amide,-   (2R,3S)-3-{[1-(2,4-difluoro-phenyl)-(7S)-(3-fluoro-benzyl)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carbonyl]-amino}-bicyclo[2.2.1]heptane-2-carboxylic    acid ethyl ester,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid N′-(2,4-dichloro-phenyl)-hydrazide,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid N′-(2,4-dichloro-phenyl)-hydrazide,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid piperidin-1-ylamide,-   (7Z)-[1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl]-piperidin-1-yl-methanone,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid pyrrolidin-1-ylamide,-   (7Z)-[1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl]-pyrrolidin-1-yl-methanone,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid [(1R,2S)-2-hydroxy-indan-1-yl]-amide,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid [(1S,2R)-2-hydroxy-indan-1-yl]-amide,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid [(1R,2R)-2-hydroxy-cyclopentyl]-amide,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid [(1R,2R)-2-hydroxy-cyclohexyl]-amide,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid [(1S)-1-phenyl-ethyl]-amide,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid [(1R)-1-phenyl-ethyl]-amide,-   4-{[(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carbonyl]-amino}-piperazine-1-carboxylic    acid tert-butyl ester,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid [(1S)-1-phenyl-ethyl]-amide,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid [(1R)-1-phenyl-ethyl]-amide,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid [(1S,2S)-2-hydroxy-cyclohexyl]-amide,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid [(1R,2S)-2-hydroxy-indan-1-yl]-amide,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid [(1S,2R)-2-hydroxy-indan-1-yl]-amide,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid (pyridin-2-ylmethyl)-amide,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5-oxo-4,5,6,7-tetrahydro-1H-5λ⁴-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid [(1R)-1-phenyl-ethyl]-amide,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5-oxo-4,5,6,7-tetrahydro-1H-5λ⁴-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid. N′-(2,4-dichloro-phenyl)-hydrazide,-   (7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-2,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid [(1R)-1-phenyl-ethyl]-amide,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5-oxo-14,5,6,7-tetrahydro-H-5λ⁴-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid piperidin-1-ylamide,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid piperidin-1-ylamide,-   (7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-2H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid [(1R)-1-phenyl-ethyl]-amide,-   (7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-2H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid piperidin-1-ylamide,-   (7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-2H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid [(1R)-1-cyclohexyl-ethyl]-amide,-   (7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-2H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid [(1S)-cyclohexyl-ethyl]-amide,-   (7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-2H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid [(1S)-1-phenyl-ethyl]-amide,-   (7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-2H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid (hexahydro-cyclopenta[c]pyrrol-2-yl)-amide,-   (7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-2,4,6,7-tetrahydro-thiopyano[4,3-c]pyrazole-3-carboxylic    acid [(1R)-1-cyclohexyl-ethyl]-amide,-   (7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid piperidin-1-ylamide,-   (7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid [(1R)-1-phenyl-ethyl]-amide,-   (7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid [(1R)-1-phenyl-ethyl]-amide,-   (7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-14,5,6,7-tetrahydro-1H-5-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid (hexahydro-cyclopenta[c]pyrrol-2-yl)-amide,-   (7Z)-[1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5-thiopyrano[4,3-c]pyrazol-3-yl]-piperidin-1-yl-methanone,-   (7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-14,5,6,7-tetrahydro-1H-5-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid piperidin-1-ylamide,-   (7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid N′-methyl-N′-phenyl-hydrazide,-   (7Z)-[1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-14,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazol-3-yl]-piperidin-1-yl-methanone,-   (7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid pyrrolidin-1-ylamide,-   (7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid (hexahydro-cyclopenta[c]pyrrol-2-yl)-amide,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid (hexahydro-cyclopenta[c]pyrrol-2-yl)-amide,-   (7Z)-1-(2,4-difluoro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid (hexahydro-cyclopenta[c]pyrrol-2-yl)-amide,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid azepan-1-ylamide,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid (2,6-dimethyl-piperidin-1-yl)-amide,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid (2,6-dimethyl-piperidin-1-yl)-amide,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid azepan-1-ylamide,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid N′-cyclohexyl-hydrazide,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid (hexahydro-cyclopenta[c]pyrrol-2-yl)-amide,-   (7Z)-7-(5-chloro-furan-2-ylmethylene)-1-(2,4-dichloro-phenyl)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid [(1R)-1-phenyl-ethyl]-amide,-   (7Z)-7-(5-chloro-furan-2-ylmethylene)-1-(2,4-dichloro-phenyl)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid [(1R)-1-cyclohexyl-ethyl]-amide,-   (7Z)-7-(5-chloro-furan-2-ylmethylene)-1-(2,4-dichloro-phenyl)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid piperidin-1-ylamide,-   (7Z)-7-(5-chloro-furan-2-ylmethylene)-1-(2,4-dichloro-phenyl)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid azepan-1-ylamide,-   (7Z)-7-(5-chloro-furan-2-ylmethylene)-1-(2,4-dichloro-phenyl)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid (hexahydro-cyclopenta[c]pyrrol-2-yl)-amide,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid [(2R)-2-(methoxymethyl)-pyrrolidin-1-yl]-amide,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid [(2S)-2-(methoxymethyl)-pyrrolidin-1-yl]-amide,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid [(1R)-1-(pyridin-2-yl)-ethyl]-amide,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid [(2S)-2-(methoxymethyl)-pyrrolidin-1-yl]-amide,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid [(2R)-2-(methoxymethyl)-pyrrolidin-1-yl]-amide,-   (7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid [(1R)-1-(pyridin-2-yl)-ethyl]-amide,-   (7Z)-(4-Bromo-benzylidene)-1-(2,4-dichloro-phenyl)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid [(1R)-1-phenyl-ethyl]-amide, and-   (7Z)-(4-Bromo-benzylidene)-1-(2,4-dichloro-phenyl)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic    acid piperidin-1-ylamide.    Syynthetic Methods

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic schemes described below and areillustrated more particularly in the specific synthetic examples thatfollow. The general schemes and specific examples are offered by way ofillustration; the invention should not be construed as being limited bythe chemical reactions and conditions expressed. The methods forpreparing the various starting materials used in the schemes andexamples are well within the skill of persons versed in the art. Noattempt has been made to optimize the yields obtained in any of theexample reactions. One skilled in the art would know how to increasesuch yields through routine variations in reaction times, temperatures,solvents and/or reagents.

The terms used in describing the invention are commonly used and knownto those skilled in the art. When used herein, the followingabbreviations have the indicated meanings:

Boc tert-butoxy carbonyl or acid t-butyl ester

(Boc)₂O di-tert-butyldicarbonate or di-t-butyl-dicarbonate

CH₂Cl₂ methylene chloride

Cpd compound

DMAP

EtOAc ethylacetate

EtOH ethanol

Et₂O diethyl ether

KOH potassium hydroxide

KOtBu potassium tert-butoxide

K₂CO₃ potassium carbonate

LDA lithium diisopropylamide

LiOH lithium hydroxide

MeOH methanol

min/hr minute(s)/hour(s)

MS Mass Spectrum shown as MS nz/z M+H⁺

NaHCO₃ sodium bicarbonate

NaIO₄ sodium periodate

Na₂SO₄ sodium sulfate

NEt₃ triethylamine

RT/rt/r.t. room temperature

TEA triethylamine

THF tetrahydrofuran

All commercially available chemicals were obtained from commercialsuppliers and used without further purification. Particular componentsor equipment used in the examples, such as reaction vessels and thelike, are also commercially available.

A substituted tetrahydro-thiopyran-4-one Compound A1 is added dropwiseto a solution of LDA (in a solvent such as anhydrous THF and the like)at −78° C. under an inert atmosphere blanket (typically using nitrogengas and the like) when the L^(a) portion of Compound A2 isdialkoxy-methane and the like. The mixture is stirred at −78° C. for 1hr, then a solution of Compound A2 (in a solvent such as anhydrous THFand the like) is added dropwise.

Alternatively, Compound A1 is added dropwise to a solution of KOtBu (ina solvent such as anhydrous THF and the like) at −78° C. under an inertatmosphere blanket when the L^(a) portion of Compound A2 isdialkoxy-methane or alkyl-carboxy and the like). The mixture is stirredand allowed to warm to r.t. for 15 hrs and the reaction is quenched(typically using water). The organic layer is diluted (in a solvent suchas EtOAc and the like), washed (with water, a dilute solution of HCl andthe like or mixtures thereof or sequentially with water and brine),separated and dried (such as with anhydrous Na₂SO₄ and the like), thenfiltered, concentrated (typically, in vacuo) and purified to yieldCompound A3.

A solution of Compound A4 (in a solvent such as MeOH and the like) isadded to a solution of Compound A3 (in a solvent such as MeOH and thelike) at a temperature of about 0° C. under an inert atmosphere. Themixture is stirred and warmed to r.t. (i.e. ambient temperature) over a15 hr period, then the reaction is quenched (typically using water) anddiluted (in a solvent such as EtOAc and the like). The organic layer iswashed (with water, a dilute solution of HCl and the like or mixturesthereof or sequentially with water and brine), separated and dried (suchas with anhydrous Na₂SO₄ and the like), then filtered, concentrated(typically, in vacuo) and optionally purified to yield Compound A5.

In many instances, substituted hydrazine compounds (of which Compound A4is representative) are commercially available in either the free base orsalt form. When not commercially available, other hydrazines may beprepared by methods known to those skilled in the art. Preferably, thesubstituted hydrazine compound used is either commercially available orprepared as a free base.

When the salt form is present, typically, the salt is either a mono- ordi-acid salt. For example, the hydrochloride or dihydrochloride salt ofCompound A4 is converted to the free base and carried forward to preparecertain compounds of the invention. The free base form of Compound A4 isprepared using techniques known to those skilled in the art. Typically,an excess of K₂CO₃ is added to a solution of the hydrochloride (1.2equivalents excess) or dihydrochloride (2.4 equivalents excess) saltform of the substituted hydrazine Compound A4 (dissolved in water), themixture is stirred at ambient temperature for up to 2 hrs. The organiclayer is extracted (using CH₂Cl₂ and the like) and dried (typicallyusing Na₂SO₄ and the like), then the mixture is filtered andconcentrated (typically in vacuo) to provide Compound A4 as a free base.

A reagent solution is added to a solution of Compound A5 (in a solventsuch as acetone and the like) at 0° C. under an inert atmosphere. WhenL^(a) is a dialkoxy-methane, the reagent solution may be 3N HCl and thelike to provide the L^(b) aldehyde. When L^(a) is an alkyl-carboxy, thereagent solution may be LiOH and the like to provide L^(b) as acarboxylic acid; the resulting L^(b) carboxylic acid may be furtherreacted with a reagent solution such as SOCl₂ and the like to provideL^(b) as a carboxyl chloride.

When the reagent solution is 3N HCl and the like, the mixture is stirredand warmed to r.t. (i.e. ambient temperature) over a period of 4 hrs,then the reaction is quenched (typically using water). The reactionmixture is neutralized to pH 7 (typically using K₂CO₃) and diluted (in asolvent such as CH₂Cl₂ and the like). The organic layer is washed(sequentially with water and brine), separated and dried (such as withanhydrous Na₂SO₄ and the like), then filtered, concentrated (typically,in vacuo) and purified to yield Compound A6 as a mixture of a major andminor isomers.

When the reagent solution is LiOH and the like, the mixture is stirredfor 24 hrs, then acidified to pH 3 (typically using 1N HCl) andextracted (typically using EtOAc). The organic layer is washed withbrine and dried over Na₂SO₄, then filtered and concentrated in vacuo toyield Compound A6 as a mixture of a major and minor isomers.

When L^(b) for Compound A6 is an aldehyde and L^(c) for Compound A7 isan alkyl reacting group and R^(a) is -Z-N(R₆)-Z₁R₇, a reagent solutionsuch as 1M KOtBu (in a solvent such as THF and the like) is addeddropwise to a solution of Compound A7 (in a solvent such as anhydrousTHF) at −78° C. under an inert atmosphere and the mixture is stirred at−78° C. for 45 min. Then a solution of Compound A6 (in a solvent such asTHF) is added dropwise. The mixture is stirred and warmed to r.t. over aperiod of 15 hrs, then the reaction is quenched (typically using water).The organic layer is diluted (in a solvent such as EtOAc and the like)and washed (with water and brine), separated and dried (such as withanhydrous Na₂SO₄ and the like), then filtered, concentrated (typically,in vacuo) and optionally purified to yield Compound A8 of Formula (I).

When L^(b) is a carboxyl chloride and L^(c) is an amine reacting groupand R^(a) is heterocyclyl or —N(R₆)-Z₁R₇ (in certain embodiments, theR^(a) heterocyclyl ring system nitrogen may be the reactive L^(c)amine), a reagent solution such as TEA (in a solvent such as DCM and thelike) is added to a solution of Compound A7 (in a solvent such asanhydrous DCM) at about r.t. under an inert atmosphere and the mixtureis stirred for 15 min.

A solution of Compound A6 (in a solvent such as DCM) is added dropwiseand the mixture is stirred at r.t. for 2 hrs. The reaction is diluted(typically with DCM) and washed (typically using water). The organiclayer is separated and dried (such as with anhydrous Na₂SO₄ and thelike), then filtered, concentrated (typically, in vacuo) and purified byflash chromatography to yield Compound A8 of Formula (I).

NaIO₄ is added to a solution of Compound B1 (in a solvent such as MeOH,THF, water and the like or mixtures thereof) at 0° C. under an inertatmosphere. The mixture is stirred and warmed to r.t. over a period of20 hrs, then the reaction is quenched and diluted (with a solvent suchas EtOAc and the like). The organic layer is washed (with water andbrine), separated and dried (such as with anhydrous Na₂SO₄ and thelike), then filtered, concentrated (typically, in vacuo) and purified toyield Compound B2.

Oxone® is added to a solution of Compound B1 (in a solvent such as MeOH,water and the like or mixtures thereof) at 0° C. under an inertatmosphere. The mixture is stirred and warmed to r.t. over a period of12 hrs, then the reaction is quenched and diluted (with a solvent suchas EtOAc and the like). The organic layer is washed (with water andbrine), separated and dried (such as with anhydrous Na₂SO₄ and thelike), then filtered, concentrated (typically, in vacuo) and purified toyield Compound B3.

The specific synthetic examples that follow herein describe morecompletely the preparation of particular compounds, which arenon-limiting illustrations of compounds intended to be included withinthe scope of the present invention. Using the procedures providedherein, one skilled in the art may prepare other compounds that aresimilarly representative of the invention by varying the startingmaterials, reagent(s) and conditions used.

EXAMPLE 1(E)-2-(1-benzyl-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl)-ethenesulfonicacid [(1R)-1-phenyl-ethyl]-amide (Cpd 7)

Tetrahydro-4H-thiopyran-4-one Compound 1a (5.0 g, 43 mmol) was addeddropwise to a solution of LDA (28.6 mL, 51.6 mmol) in anhydrous THF (50mL) at −78° C. under a N₂ atmosphere. The mixture was stirred at −78° C.for 1 hr, then dimethoxy-acetic acid methyl ester Compound 1b (5.78 g,43.0 mmol) in anhydrous THF (5 mL) was added dropwise. The solution wasstirred and warmed to r.t. over a 15 hr period, then the reaction wasquenched with water (5 mL). The organic layer was diluted with EtOAc(200 mL) and washed with water and brine, separated and dried withanhydrous Na₂SO₄, then filtered and concentrated in vacuo to yield acrude oil, which was purified by flash chromatography (eluted with 10%EtOAc in hexane) to afford Compound 1c (6.56 g, 70%).

An excess of K₂CO₃ (7.5 g) was added to a solution of benzylhydrazinedihydrochloride (7.00 g, 35.9 mmol) in Et₂O (100 mL). The mixture wasstirred at ambient temperature for 2 hrs and the reaction was quenchedwith water (20 mL). The organic layer was washed with water and brineand dried with anhydrous Na₂SO₄, then filtered and concentrated in vacuoto yield benzylhydrazine Compound 1d (4.17 g, 34.2 mmol).

Benzylhydrazine Compound 1d (3.63 g, 29.8 mmol) in MeOH (10 mL) wasadded to a solution of Compound 1c (6.5 g, 30 mmol) in MeOH (75 mL) at0° C. under a N₂ atmosphere. The mixture was stirred and warmed to r.t.over a 15 hr period. The reaction was quenched with water (20 mL) anddiluted with EtOAc (200 mL). The organic layer was washed with water andbrine, separated and dried with anhydrous Na₂SO₄, then filtered andconcentrated in vacuo to yield a crude oil, which was purified by flashchromatography (eluted with 10% EtOAc in hexane) to afford a mixture ofa major isomer Compound 1e and a minor isomer Compound 1f (6.76 g, 75%).

3N HCl (8 mL) was added to a solution of the mixture of Compound 1e andCompound 1f (6.5 g, 21 mmol) in acetone (50 mL) at 0° C. under a N₂atmosphere. The mixture was stirred and warmed to r.t. over a 4 hrperiod. The reaction was quenched with water (20 mL), neutralized to pH7 with K₂CO₃ and diluted with CH₂Cl₂ (100 mL). The organic layer waswashed with water and brine, separated and dried with anhydrous Na₂SO₄,then filtered and concentrated in vacuo to yield a crude oil, which waspurified by flash chromatography (eluted with 10% EtOAc in hexane) toyield a major isomer carbaldehyde Compound 1g (3.49 g, 63%) and a minorisomer carbaldehyde Compound 1h (1.75 g, 31%) as a colorless oil.

NEt₃ (2.43 mL, 17.46 mmol) and methanesulfonyl chloride Compound 1i (2.0g, 17 mmol) were added to a solution of(a¹R)-α-methyl-benzenemethanamine Compound 1j (1.75 g, 17.5 mmol) at 0°C. under a N₂ atmosphere. The mixture was stirred and warmed to r.t.over a 3 hr period, then the reaction was quenched with water (5 mL).The organic layer was diluted with CH₂Cl₂ (100 mL) and washed with waterand brine, separated and dried with anhydrous Na₂SO₄, then filtered andconcentrated in vacuo to afford the corresponding sulfonamide Compound1k as an oil.

Di-tert-butyldicarbonate (4.57 g, 21.0 mmol) and DMAP (8 mg) were addedto a solution of Compound 1k in CH₂Cl₂ (10 mL) at 0° C. under a N₂atmosphere. The mixture was stirred and warmed to r.t. overnight, thenthe reaction was quenched with a saturated solution of NaHCO₃ (10 mL).The organic layer was diluted with CH₂Cl₂ (100 mL) and washed with waterand brine, separated and dried with anhydrous Na₂SO₄, then filtered andconcentrated in vacuo to yield a crude Boc-protectedmethanesulphonamide, which was purified by flash chromatography using10% EtOAc in hexane to afford Compound 1l (3.89 g, 80%) as a colorlessoil (the preceding method was an adaption of the procedure described inTozer M J, Woolford A J A and Linney I A, Synlett, 1998, 2, 186-188).

A 1M solution of KOtBu in THF (0.75 mL, 0.75 mmol) was added dropwise toa solution of Compound 1l (0.050 g, 0.250 mmol) in anhydrous THF (5 mL)at −78° C. under a N₂ atmosphere. The mixture was stirred for 45 min,then1-benzyl-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carbaldehydeCompound 1g (0.116 g, 0.250 mmol) diluted in THF (3 mL) was addeddropwise. The mixture was warmed to ambient temperature over a period of15 hrs, then the reaction was quenched with water (5 mL). The organiclayer was diluted with EtOAc (100 mL) and washed with water and brine,separated and dried with anhydrous Na₂SO₄, then filtered andconcentrated in vacuo to yield a crude product, which was purified byflash chromatography (eluted with 20% EtOAc in hexane) to give Compound7 (0.082 g, 75%) as a white solid. MS m/z 440.1 (MH⁺); ¹H NMR (CDCl₃,400 MHz) δ 7.43-7.15 (m, 11H), 6.73 (d, J=8.4 Hz, 1H), 6.44 (d, J=15.7Hz, 1H), 5.30 (s, 2H), 4.59-4.54 (m, 1H), 3.41 (s, 2H), 2.91 (s, 2H),1.51 (d, J=7.0 Hz, 3H).

Using the procedure of Example 1, other compounds that arerepresentative of the invention may be prepared by varying the startingmaterials, reagent(s) and conditions used, such as: Cpd Name MS 11(E)-2-(1-benzyl-1,4,6,7-tetrahydro- 446.1thiopyrano[4,3-c]pyrazol-3-yl)-ethenesulfonic acid[(1R)-1-cyclohexyl-ethyl]-amide

EXAMPLE 2(E)-2-(1-benzyl-5-oxo-4,5,6,7-tetrahydro-1H-5λ⁴-thiopyrano[4,3-c]pyrazol-3-yl)-ethenesulfonicacid [(1R)-1-phenyl-ethyl]-amide (Cpd 30)

NaIO₄ (0.038 g, 0.18 mmol) was added to a solution of amide Compound 7(0.04 g, 0.09 mmol) in a mixture of MeOH, THF and water (4 mL) (1:1:2)at 0° C. under a N₂ atmosphere. The mixture was stirred and warmed toambient temperature over a 20 hr period, then diluted with EtOAc. Theorganic layer was washed with water and brine, dried with anhydrousNa₂SO₄, then filtered and concentrated in vacuo to yield a crude oil,which was purified by flash chromatography to afford Compound 30 (0.032g, 80%) as a white solid. MS m/z 456 (MH⁺).

Using the procedure of Example 2, other compounds that arerepresentative of the invention may be prepared by varying the startingmaterials, reagent(s) and conditions used, such as: Cpd Name MS 211-benzyl-5-oxo-4,5,6,7-tetrahydro-1H-5λ⁴-thiopyrano[4,3-c]pyrazole-3-426 carboxylic acid (1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl)-amide 22(E)-2-(2-benzyl-5-oxo-4,5,6,7-tetrahydro-2H-5λ⁴-thiopyrano[4,3-c]pyrazol-456.1 3-yl)-ethenesulfonic acid (1-phenyl-ethyl)-amide 23(E)-2-(2-benzyl-5-oxo-4,5,6,7-tetrahydro-2H-5λ⁴-thiopyrano[4,3-c]pyrazol-456.1 3-yl)-ethenesulfonic acid [(1R)-1-phenyl-ethyl]-amide 24(E)-2-(2-benzyl-5-oxo-4,5,6,7-tetrahydro-2H-5λ⁴-thiopyrano[4,3-c]pyrazol-456.1 3-yl)-ethenesulfonic acid [(1S)-1-phenyl-ethyl]-amide 25(E)-2-(1-benzyl-5-oxo-4,5,6,7-tetrahydro-1H-5λ⁴-thiopyrano[4,3-c]pyrazol-462.1 3-yl)-ethenesulfonic acid (1-cyclohexyl-ethyl)amide 26(E)-2-(2-benzyl-5-oxo-4,5,6,7-tetrahydro-2H-5λ⁴-thiopyrano[4,3-c]pyrazol-462.1 3-yl)-ethenesulfonic acid (1-cyclohexyl-ethyl)-amide 27(E)-2-(2-benzyl-5-oxo-4,5,6,7-tetrahydro-2H-5λ⁴-thiopyrano[4,3-c]pyrazol-462.1 3-yl)-ethenesulfonic acid [(1R)-1-cyclohexyl-ethyl]-amide 28(E)-2-(2-benzyl-5-oxo-4,5,6,7-tetrahydro-2H-5λ⁴-thiopyrano[4,3-c]pyrazol-462.1 3-yl)-ethenesulfonic acid [(1S)-1-cyclohexyl-ethyl]-amide 29(E)-2-(1-benzyl-5-oxo-4,5,6,7-tetrahydro-1H-5λ⁴-thiopyrano[4,3-c]pyrazol-456 3-yl)-ethenesulfonic acid (1-phenyl-ethyl)-amide 31(E)-2-(1-benzyl-5-oxo-4,5,6,7-tetrahydro-1H-5λ⁴-thiopyrano[4,3-c]pyrazol-456 3-yl)-ethenesulfonic acid [(1S)-1-phenyl-ethyl]-amide 34(2E)-3-(1-benzyl-5-oxo-4,5,6,7-tetrahydro-1H-5λ⁴-thiopyrano[4,3- 420.1c]pyrazol-3-yl)-N-[(1S)-1-phenyl-ethyl]-acrylamide 35(2E)-3-(1-benzyl-5-oxo-4,5,6,7-tetrahydro-1H-5λ⁴-thiopyrano[4,3- 420.1c]pyrazol-3-yl)-N-[(1R)-1-phenyl-ethyl]-acrylamide 74(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5-oxo-4,5,6,7- 554tetrahydro-1H-5λ⁴-thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1S)-1-phenyl-ethyl]-amide 75(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5-oxo-4,5,6,7- 554tetrahydro-1H-5λ⁴-thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1R)-1-phenyl-ethyl]-amide 76(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5-oxo-4,5,6,7-558(+Na) tetrahydro-1H-5λ⁴-thiopyrano[4,3-c]pyrazole-3-carboxylic acid[(1R,2R)-2- hydroxy-cyclopentyl]-amide 77(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5-oxo-4,5,6,7- 612tetrahydro-1H-5λ⁴-thiopyrano[4,3-c]pyrazole-3-carboxylic acid N′-(2,4-dichloro-phenyl)-hydrazide 79(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5-oxo-4,5,6,7-533.1 tetrahydro-1H-5λ⁴-thiopyrano[4,3-c]pyrazole-3-carboxylic acidpiperidin-1- ylamide 80(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5-oxo-4,5,6,7- 541tetrahydro-1H-5λ⁴-thiopyrano[4,3-c]pyrazole-3-carboxylic acid(pyridin-2- ylmethyl)-amide 96(7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-5-oxo-4,5,6,7- 499.2tetrahydro-1H-5λ⁴-thiopyrano[4,3-c]pyrazole-3-carboxylic acidpiperidin-1- ylamide

EXAMPLE 3(E)-2-(1-benzyl-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4-3-c]pyrazol-3-yl)-ethenesulfonicacid [(1R)-1-phenyl-ethyl]-amide (Cpd 9)

Oxone® (0.202 g, 0.330 mmol) was added to a solution of Compound 7 (0.05g, 0.11 mmol) in a mixture of MeOH and water (1:1) at 0° C. under a N₂atmosphere. The solution was stirred and warmed to ambient temperatureover a 12 hr period, then diluted with EtOAc. The organic layer waswashed with water and brine and dried with anhydrous Na₂SO₄, thenfiltered and concentrated in vacuo to yield a crude oil, which waspurified by flash chromatography to afford Compound 9 (0.049 g, 95%) asa white solid. MS m/z 472.1 (MH⁺); ¹H NMR (CDCl₃, 400 MHz) δ 7.38-7.15(m, 11H), 6.78 (d, J=9.1 Hz, 1H), 6.21 (d, J=15.5 Hz, 1H), 5.42 (s, 2H),4.44-4.39 (m, 1H), 3.31 (dd, J=15.6, 15.8 Hz, 1H), 2.87-2.80 (m, 6H),1.44 (d, J=7.0 Hz, 3H).

Using the procedure of Example 3, other compounds that arerepresentative of the invention may be prepared by varying the startingmaterials, reagent(s) and conditions used, such as: Cpd Name MS 4(E)-2-(2-benzyl-5,5-dioxo-4,5,6,7-tetrahydro-2H-5λ⁶-thiopyrano[4,3-472.2 c]pyrazol-3-yl)-ethenesulfonic acid [(1R)-1-phenyl-ethyl]-amide 10(E)-2-(2-benzyl-5,5-dioxo-4,5,6,7-tetrahydro-2H-5λ⁶-thiopyrano[4,3- 472c]pyrazol-3-yl)-ethenesulfonic acid [(1S)-1-phenyl-ethyl]-amide 131-benzyl-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-410 3-carboxylic acid [(1R)-1-phenyl-ethyl]-amide 14(E)-2-(1-benzyl-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3- 478c]pyrazol-3-yl)-ethenesulfonic acid [(1R)-1-cyclohexyl-ethyl]-amide 15(E)-2-(1-benzyl-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3- 478c]pyrazol-3-yl)-ethenesulfonic acid [(1S)-1-cyclohexyl-ethyl]-amide 16(E)-2-(2-benzyl-5,5-dioxo-4,5,6,7-tetrahydro-2H-5λ⁶-thiopyrano[4,3-478.2 c]pyrazol-3-yl)-ethenesulfonic acid[(1R)-1-cyclohexyl-ethyl]-amide 17(E)-2-(2-benzyl-5,5-dioxo-4,5,6,7-tetrahydro-2H-5λ⁶-thiopyrano[4,3-478.2 c]pyrazol-3-yl)-ethenesulfonic acid[(1S)-1-cyclohexyl-ethyl]-amide 18(E)-2-(1-benzyl-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-472.1 c]pyrazol-3-yl)-ethenesulfonic acid [(1S)-1-phenyl-ethyl]-amide 201-benzyl-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-442 3-carboxylic acid (1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl)-amide 36(2E)-3-(1-benzyl-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3- 436c]pyrazol-3-yl)-N-[(1S)-1-phenyl-ethyl]-acrylamide 37(2E)-3-(1-benzyl-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3- 436c]pyrazol-3-yl)-N-[(1R)-1-phenyl-ethyl]-acrylamide 42(E)-2-[1-(2,4-difluoro-phenyl)-7-(3-fluoro-benzyl)-5,5-dioxo-4,5,6,7-602.1 tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazol-3-yl]-ethenesulfonicacid [(1S)-1-phenyl-ethyl]-amide 43(E)-2-[1-(2,4-difluoro-phenyl)-7-(3-fluoro-benzyl)-5,5-dioxo-4,5,6,7-608.1 tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazol-3-yl]-ethenesulfonicacid [(1R)-1-cyclohexyl-ethyl]-amide 44(E)-2-[1-(2,4-difluoro-phenyl)-7-(3-fluoro-benzyl)-5,5-dioxo-4,5,6,7-583 tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazol-3-yl]-ethenesulfonic acidmorpholin-4-ylamide 45(E)-2-[1-(2,4-difluoro-phenyl)-7-(3-fluoro-benzyl)-5,5-dioxo-4,5,6,7-579.2 tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazol-3-yl]-ethenesulfonicacid piperidin-1-ylamide 49(2R,3S)-3-{[1-(2,4-difluoro-phenyl)-(7R)-(3-fluoro-benzyl)-5,5-dioxo-602.14,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carbonyl]-amino}-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester 50(2R,3S)-3-{[1-(2,4-difluoro-phenyl)-(7S)-(3-fluoro-benzyl)-5,5-dioxo-602.14,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carbonyl]-amino}-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester 511-(2,4-difluoro-phenyl)-7-(3-fluoro-benzyl)-5,5-dioxo-4,5,6,7-tetrahydro-568 1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acid[(1R,2S)-2-hydroxy- indan-1-yl]-amide 53(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-627 tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acidN′-(2,4- dichloro-phenyl)-hydrazide 65(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-570 tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acid[(1S)-1- phenyl-ethyl]-amide 66(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-570 tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acid[(1R)-1- phenyl-ethyl]-amide 67(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-550 tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acid[(1R,2R)- 2-hydroxy-cyclopentyl]-amide 68(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-564 tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acid[(1S,2S)-2- hydroxy-cyclohexyl]-amide 69(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-598 tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acid[(1R,2S)- 2-hydroxy-indan-1-yl]-amide 70(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-598 tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acid[(1S,2R)- 2-hydroxy-indan-1-yl]-amide 71(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-465 tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acid amide73(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-557.1 tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acid(pyridin-2- ylmethyl)-amide 81(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-549.1 tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acidpiperidin- 1-ylamide 82(7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-571.1 tertahydro-2H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acid[(1R)-1- phenyl-ethyl]-amide 83(7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-549 tetrahydro-2H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acidpiperidin- 1-ylamide 84(7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-576.2 tetrahydro-2H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acid[(1R)-1- cyclohexyl-ethyl]-amide 85(7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-571.2 tetrahydro-2H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acid[(1S)-1- cyclohexyl-ethyl]-amide 86(7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-571 tetrahydro-2H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acid[(1S)-1- phenyl-ethyl]-amide 87(7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-575.1 tetrahydro-2H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acid(hexahydro-cyclopenta[c]pyrrol-2-yl)-amide 95(7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7- 536tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1R)-1-phenyl-ethyl]-amide 97(7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7- 541tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acid(hexahydro-cyclopenta[c]pyrrol-2-yl)-amide 98(7Z)-[1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-499 tetrahydro-1H-5λ⁶-thiopyranol[4,3-c]pyrazol-3-yl]-piperidin-1-yl-methanone 99(7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7- 515tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acid piperidin-1-ylamide 100(7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-536.9 tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acidN′-methyl- N′-phenyl-hydrazide 101(7Z)-[1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-534 tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazol-3-yl]-piperidin-1-yl-methanone 104(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-576 tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acid(hexahydro-cyclopenta[c]pyrrol-2-yl)-amide 105(7Z)-1-(2,4-difluoro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-543.2 tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acid(hexahydro-cyclopenta[c]pyrrol-2-yl)-amide 106(7Z)-1-(2,4-difluoro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-517.2 tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acidpiperidin- 1-ylamide 107(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-563.1 tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acidazepan-1- ylamide 108(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-577 tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acid (2,6-dimethyl-piperidin-1-yl)-amide 109(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-566.1 tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acid(4-methyl- piperazin-1-yl)-amide 110(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-595 tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxoylic acid[4-(2- hydroxy-ethyl)-piperazin-1-yl]-amide 117(7Z)-7-(5-chloro-furan-2-ylmethylene)-1-(2,4-dichloro-phenyl)-5,5-dioxo-575.8 4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylicacid [(1R)-1-phenyl-ethyl]-amide 118(7Z)-7-(5-chloro-furan-2-ylmethylene)-1-(2,4-dichloro-phenyl)-5,5-dioxo-583.9 4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylicacid [(1R)-1-cyclohexyl-ethyl]-amide 119(7Z)-7-(5-chloro-furan-2-ylmethylene)-1-(2,4-dichloro-phenyl)-5,5-dioxo-554.8 4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylicacid piperidin-1-ylamide 120(7Z)-7-(5-chloro-furan-2-ylmethylene)-1-(2,4-dichloro-phenyl)-5,5-dioxo-569.1 4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylicacid azepan-1-ylamide 121(7Z)-7-(5-chloro-furan-2-ylmethylene)-1-(2,4-dichloro-phenyl)-5,5-dioxo-581 4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylicacid (hexahydro-cyclopenta[c]pyrrol-2-yl)-amide 124(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7571 tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acid[(1R)-1- (pyridin-2-yl)-ethyl]-amide 125(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-579 tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acid[(2S)-2- (methoxymethyl)-pyrrolidin-1-yl]-amide 126(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-579 tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acid[(2R)-2- (methoxymethyl)-pyrrolidin-1-yl]-amide 1281-(2,4-dichloro-phenyl)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶- 464thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1R)-1-phenyl-ethyl]-amide

EXAMPLE 4(E)-2-(1-benzyl-1,4,6,7-tetrahydro-thiopyrano[4-3-c]pyrazol-3-yl)-ethenesulfonicacid [(1S)-1-phenyl-ethyl]-amide (Cpd 3)

Using the adapted Tozer procedure of Example 1, NEt₃ and methanesulfonylchloride Compound 1i were added to a solution of(α¹S)-α-methyl-benzenemethanamine Compound 4a at 0° C. under a N₂atmosphere. The mixture was stirred and warmed to ambient temperatureover a 3 hr period, then the reaction was quenched with water. Theorganic layer was diluted with CH₂Cl₂, washed with water and brine, thenseparated and dried with anhydrous Na₂SO₄. The product was filtered andconcentrated in vacuo to afford aN-[(1S)-1-phenyl-ethyl)-methanesulfonamide Compound 4b as an oil.

Di-t-butyl-dicarbonate and DMAP were added to a solution of Compound 4bin CH₂Cl₂ at 0° C. under a N₂ atmosphere. The mixture was stirred andwarmed to ambient temperature overnight, then the reaction was quenchedwith a saturated solution of NaHCO₃. The organic layer was diluted withCH₂Cl₂ and washed with water and brine, separated and dried withanhydrous Na₂SO₄, then filtered and concentrated in vacuo to yield acrude product, which was purified by flash chromatography (eluted with10% EtOAc in hexane) to afford N-(t-butoxycarbonyl)-N-[(1S)-1-phenyl-ethyl]-methanesulfonamide Compound 4c as acolorless oil.

A 1M solution of KOtBu in THF (0.80 mL, 0.80 mmol) was added dropwise toa solution of methanesulfonamide Compound 4c (0.120 mg, 0.40 mmol) inanhydrous THF (10 mL) at −78° C. under a N₂ atmosphere. The mixture wasstirred for about 45 min, then carbaldehyde Compound 1g (0.100 g, 0.4mmol) diluted in THF (3 mL) was added dropwise. The mixture was warmedto ambient temperature over a 15 hr period, then the reaction wasquenched with water (5 mL). The organic layer was diluted with EtOAc(100 mL), washed with water and brine, separated and dried withanhydrous Na₂SO₄, then filtered and concentrated in vacuo to yield acrude product, which was purified by flash chromatography (eluted with20% EtOAc in hexane) to give Compound 3 (0.134 g, 76%) as a white solid.MS m/z 440.1 (MH⁺).

Using the procedure of Example 4, other compounds that arerepresentative of the invention may be prepared by varying the startingmaterials, reagent(s) and conditions used, such as: Cpd Name MS 12(E)-2-(1-benzyl-1,4,6,7-tetrahydro- 446.1thiopyrano[4,3-c]pyrazol-3-yl)-ethenesulfonic acid[(1S)-1-cyclohexyl-ethyl]-amide

EXAMPLE 5(E)-2-(2-benzyl-2,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl)-ethenesulfonicacid [(1R)-1-phenyl-ethyl]-amide (Cpd 2)

A 1M solution of KOtBu in THF (0.75 mL, 0.75 mmol) was added dropwise toa solution of Compound 1l (0.050 g, 0.250 mmol) in anhydrous THF (5 mL)at −78° C. under a N₂ atmosphere. After 45 min,2-benzyl-2,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carbaldehydeCompound 1h (0.116 g, 0.250 mmol) diluted in THF (3 mL) was addeddropwise. The solution was warmed to ambient temperature over a 15 hrperiod, then the reaction was quenched with water (5 mL). The organiclayer was diluted with EtOAc (100 mL) and washed with water and brine,separated and dried with anhydrous Na₂SO₄, then filtered andconcentrated in vacuo to yield a crude product, which was purified byflash chromatography (eluted with 20% EtOAc in hexane) to give Compound2 (0.082 g, 75%) as a white solid. MS m/z 440.1 (MH⁺).

Using the procedure of Example 5, other compounds that arerepresentative of the invention may be prepared by varying the startingmaterials, reagent(s) and conditions used, such as: Cpd Name MS 6(E)-2-(2-benzyl-2,4,6,7-tetrahydro-thiopyrano[4,3- 446.3c]pyrazol-3-yl)-ethenesulfonic acid [(1R)-1-cyclohexyl- ethyl]-amide

EXAMPLE 6(E)-2-(2-benzyl-2,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl)-ethenesulfonicacid [(1S)-1-phenyl-ethyl]-amide (Cpd 5)

A 1M solution of KOtBu in THF (1.6 mL, 1.6 mmol) was added dropwise to asolution of methanesulfonamide Compound 4c (0.220 g, 0.74 mmol) inanhydrous THF (10 mL) at −78° C. under a N₂ atmosphere. After 45 mins,carbaldehyde Compound 1h (0.190 g, 0.74 mmol) diluted in THF (3 mL) wasadded dropwise. The solution was warmed to ambient temperature and thereaction was quenched with water (5 mL). The organic layer was dilutedwith EtOAc (100 mL) and washed with water and brine, separated and driedwith anhydrous Na₂SO₄, then filtered and concentrated in vacuo to yielda crude product, which was purified by flash chromatography (eluted with20% EtOAc in hexane) to give Compound 5 (0.230 g, 71%). MS m/z 440.1(MH⁺).

Using the procedure of Example 6, other compounds that arerepresentative of the invention may be prepared by varying the startingmaterials, reagent(s) and conditions used, such as: Cpd Name MS 8(E)-2-(2-benzyl-2,4,6,7-tetrahydro-thiopyrano[4,3- 446.1c]pyrazol-3-yl)-ethenesulfonic acid [(1S)-1-phenyl-ethyl]- amide

EXAMPLE 7(2E)-3-(1-benzyl-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl)-N-[(1S)-1-phenyl-ethyl]-acrylamide(Cpd 32)

Acetyl chloride Compound 7a (0.70 g, 8.90 mmol) and TEA (0.90 g) wereadded to a solution of (α¹S)-α-methyl-benzenemethanamine Compound 4a(1.0 g, 8.2 mmol) in CH₂Cl₂ (12 mL) at 0° C. under a N₂ atmosphere. Themixture was stirred and warmed to r.t. over a 2 hr period, then thereaction was quenched with water (50 mL). The organic layer was dilutedwith CH₂Cl₂ (50 mL) and washed with water and brine, separated and driedwith anhydrous Na₂SO₄, then filtered and concentrated in vacuo to affordthe corresponding N-(1S)-1-phenyl-ethyl-acetamide Compound 7b as an oil.

(Boc)₂O (1.48 g, 6.45 mmol) and DMAP (100 mg) were added to a solutionof the acetamide Compound 7b in CH₂Cl₂ (16 mL) at 0° C. under a N₂atmosphere. The mixture was stirred and warmed to r.t. overnight, thenthe reaction was quenched with a saturated solution of NaHCO₃ (10 mL).The organic layer was diluted with CH₂Cl₂ (50 mL) and washed with waterand brine, separated and dried with anhydrous Na₂SO₄, then filtered andconcentrated in vacuo to yield a crude product, which was purified byflash chromatography (eluted with 20% EtOAc in hexane) to affordacetyl-(1S)-1-phenyl-ethyl-carbamic acid tert-butyl ester Compound 7c(0.4 g, 24%) as an oil.

Using the adapted Tozer procedure of Example 1, a 1M solution of KOtBuin THF (1.2 mL, 1.2 mmol) was added dropwise to a solution of Compound7c (0.08 g, 0.30 mmol) in anhydrous THF (6 mL) at −78° C. under a N₂atmosphere. After about 30 min, Compound 1g (0.07 g, 0.30 mmol) dilutedin THF (2 mL) was added dropwise. The mixture was stirred and warmed tor.t. over an 18 hr period, then the reaction was quenched with water (2mL). The organic layer was diluted with EtOAc (10 mL) and washed withwater and brine, separated and dried with anhydrous Na₂SO₄, thenfiltered and concentrated in vacuo to yield a crude product, which waspurified by flash chromatography (eluted with 25% EtOAc in hexane) togive Compound 32 (0.093 g, 77%) as a solid. MS m/z 403.1 (MH⁺).

EXAMPLE 8(2E)-3-(1-benzyl-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl)-N-[(1R)-1-phenyl-ethyl]-acrylamide(Cpd 33)

Acetyl chloride Compound 7a (0.8 g, 10 mmol) and TEA were added to asolution of (α¹R)-α-methyl-benzenemethanamine Compound 1h (1.2 g, 10mmol) in CH₂Cl₂ (12 m]L) at −0° C. under a N₂ atmosphere. The mixturewas stirred and warmed to r.t., then the reaction was quenched withwater (30 mL). The organic layer was diluted with CH₂Cl₂ (50 mL) andwashed with water and brine, separated and dried with anhydrous Na₂SO₄,then filtered and concentrated in vacuo to afford the correspondingN-(1S)-1-phenyl-ethyl-acetamide Compound 8a as oil.

(Boc)₂O (2.18 g) and DMAP (100 mg) were added to a solution of theacetamide Compound 8a in CH₂Cl₂ (16 mL) at 0° C. under a N₂ atmosphere.The mixture was stirred overnight while warming to r.t., then thereaction was quenched with a saturated solution of NaHCO₃ (10 mL). Theorganic layer was diluted with CH₂Cl₂ (50 mL) and washed with water andbrine, separated and dried with anhydrous Na₂SO₄, then filtered andconcentrated in vacuo to yield a crude product, which was purified byflash chromatography (eluted with 20% EtOAc in hexane) to affordacetyl-(1S)-1-phenyl-ethyl-carbamic acid tert-butyl ester Compound 8b(0.6 g, 23%) as an oil.

Using the adapted Tozer procedure of Example 1, a solution of KOtBu inTHF (2.5 mL, 2.5 mmol) was added dropwise to a solution of thetert-butyl ester Compound 8b (0.26 g, 1.0 mmol) in anhydrous THF (10 mL)at −78° C. under a N₂ atmosphere. After 45 min. Compound 1g (0.25 g, 1.0mmol) diluted in THF (3 mL) was added dropwise. The mixture was stirredand warmed to r.t. over an 18 hr period, then the reaction was quenchedwith water (10 mL). The organic layer was diluted with EtOAc (100 mL)and washed with water and brine, separated and dried with anhydrousNa₂SO₄, then filtered and concentrated in vacuo to yield a crudeproduct, which was purified by flash chromatography (eluted with 25%EtOAc in hexane) to give Compound 33 (0.25 g, 62%) as a solid. MS m/z404.1 (MH⁺).

EXAMPLE 9(E)-2-[7-(3-fluoro-benzyl)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl]-ethenesulfonicacid [(1S)-1-phenyl-ethyl]-amide (Cpd 47)

3-(3-Fluoro-phenyl)-tetrahydro-4H-thiopyran-4-one Compound 9a (2.24 g,10 mmol) was added dropwise to a solution of LDA in anhydrous THF (60mL) at −78° C. under a N₂ atmosphere. The mixture was stirred at −78° C.for 30 mins, and dimethoxy-acetic acid methyl ester Compound 1b (1.3 g,10 mmol) in anhydrous THF (5 mL) was added dropwise. The solution wasstirred and warmed to r.t. over a 12 hr period, then the reaction wasquenched with water (10 mL). The organic layer was diluted with EtOAc(100 mL) and washed with water and brine, separated and dried withanhydrous Na₂SO₄, then filtered and concentrated in vacuo to yield acrude oil, which was purified by flash chromatography (eluted with 5%EtOAc in hexane) to afford3-(2,2-dimethoxy-acetyl)-5-(3-fluoro-phenyl)-tetrahydro-4H-thiopyran-4-oneCompound 9b (2.1 g, 64%) as an oil.

Hydrazine Compound 9c (0.2 g, 6.5 mmol) was added to a solution ofCompound 9b (2.1 g, 6.4 mmol) in MeOH (60 mL) at 0° C. under a N₂atmosphere. The solution was stirred and warmed to r.t. over a 16 hrperiod. The reaction was quenched with water (50 mL) and diluted withEtOAc (100 mL). The organic layer was washed with water and brine,separated and dried with anhydrous Na₂SO₄, then filtered andconcentrated in vacuo to yield a crude oil, which was purified by flashchromatography (eluted with 30% EtOAc in hexane) to afford a white solidmixture of3-dimethoxymethyl-7-(4-fluoro-benzyl)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazoleCompound 9d (1.2 g, 57%) as the major isomer and3-dimethoxymethyl-7-(4-fluoro-benzyl)-2,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazoleCompound 9e as the minor isomer.

3N HCl (1.0 mL) was added to a solution of the mixture of Compound 9d(1.2 g, 3.7 mmol) in acetone (40 mL) at 0° C. under a N₂ atmosphere. Thesolution was stirred and warmed to r.t. over a 2 hr period. The reactionwas neutralized to pH 7 with K₂CO₃ and diluted with CH₂Cl₂ (60 mL). Theorganic layer was washed with water and brine, separated and dried withanhydrous Na₂SO₄, then filtered and concentrated in vacuo to yield acrude oil, which was purified by flash chromatography (eluted with 10%EtOAc in hexane) to yield7-(3-fluoro-phenyl)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carbaldehydeCompound 9f (0.95 g, 93%) as a solid.

A 1.0M solution of KOtBu in THF (1.7 mL, 1.7 mmol) was added dropwise toa solution of methanesulfonamide Compound 4c (0.21 g, 0.70 mmol) inanhydrous THF (15 mL) at −78° C. under a N₂ atmosphere. The mixture wasstirred for about 30 min, then carbaldehyde Compound 9f (0.19 g, 0.70mmol) diluted in THF (3 mL) was added dropwise. The mixture was warmedto ambient temperature over an 18 hr period, then the reaction wasquenched with water (10 mL). The organic layer was diluted with EtOAc(100 mL) and washed with water and brine, separated and dried withanhydrous Na₂SO₄, then filtered and concentrated in vacuo to yield acrude product, which was purified by flash chromatography (eluted with25% EtOAc in hexane) to provide Compound 47 (0.20 g, 65%) as a whitesolid. MS m/z 458 (MH⁺).

EXAMPLE 10(E)-2-[1-(2,4-difluoro-phenyl)-7-(3-fluoro-benzyl)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl]-ethenesulfonicacid [(1S)-1-phenyl-ethyl]-amide (Cpd 38)

Anhydrous 2,4-difluorophenylhydrazine hydrochloride Compound 10a (0.9 g,4.9 mmol) and K₂CO₃ (0.78 g, 5.6 mmol) were added to a solution ofCompound 9b (1.6 g, 4.9 mmol) in EtOH (20 mL). The mixture was stirredat r.t. for a 16 hr period, filtered and washed with EtOH, thenconcentrated and purified on a silica gel column (eluted with 20% EtOAcin hexane) to afford Compound 10b (1.34 g, 62%) as a white solid.

3N HCl (2 mL) was added to a solution of Compound 10b (1.34 g, 3.1 mmol)in acetone (20 mL) at 0° C. under a N₂ atmosphere. The solution wasstirred and warmed to r.t. over a 3 hr period. The reaction was quenchedwith water (10 mL), neutralized to pH 7 with K₂CO₃ and diluted withCH₂Cl₂ (60 mL). The organic layer was washed with water and brine,separated and dried with anhydrous Na₂SO₄, then filtered andconcentrated in vacuo to yield a crude oil, which was purified by flashchromatography (eluted with 10% EtOAc in hexane) to yield1-(2,4-difluoro-phenyl)-7-(3-fluoro-phenyl)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carbaldehydeCompound 10c (1.1 g, 91%) as a white solid.

A 1.0M solution of KOtBu in THF (0.4 mL, 0.4 mmol) was added dropwise toa solution of methanesulfonamide Compound 4c (0.045 g, 0.15 mmol) inanhydrous THF (5 mL) at −78° C. under a N₂ atmosphere. The mixture wasstirred for 45 min, then carbaldehyde Compound 10c (0.06 g, 0.15 mmol)diluted in THF (2.5 mL) was added dropwise. The mixture was warmed toambient temperature over an 18 hr period, then the reaction was quenchedwith water (5 mL). The organic layer was diluted with EtOAc (25 mL) andwashed with water and brine, separated and dried with anhydrous Na₂SO₄,then filtered and concentrated in vacuo to yield a crude product, whichwas purified by flash chromatography (eluted with 25% EtOAc in hexane)to provide Compound 38 (0.058 g, 68%) as a white solid. MS m/z 570.2(MH⁺).

Using the procedure of Example 10, other compounds that arerepresentative of the invention may be prepared by varying the startingmaterials, reagent(s) and conditions used, such as: Cpd Name MS 39(E)-2-[1-(2,4-difluoro-phenyl)-7-(3-fluoro-benzyl)-1,4,6,7-tetrahydro-576 thiopyrano[4,3-c]pyrazol-3-yl]-ethenesulfonic acid[(1R)-1-cyclohexyl- ethyl]-amide 40(E)-2-[1-(2,4-difluoro-phenyl)-7-(3-fluoro-benzyl)-1,4,6,7-tetrahydro-549.2 thiopyrano[4,3-c]pyrazol-3-yl]-ethenesulfonic acidpiperidin-1-ylamide 46(E)-2-[7-(3-chloro-benzy)-1-(2,4-dichloro-phenyl)-1,4,6,7-tetrahydro-619 thiopyrano[4,3-c]pyrazol-3-yl]-ethenesulfonic acid[(1S)-1-phenyl-ethyl]- amide 48(E)-2-[7-(3-fluoro-benzyl)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-464.1 yl]-ethenesulfonic acid [(1R)-1-cyclohexyl-ethyl]-amide

EXAMPLE 11(E)-2-[1-(2,4-difluoro-phenyl)-7-(3-fluoro-benzyl)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl]-ethenesulfonicacid morpholin-4-ylamide (Cpd 41)

Using the adapted Tozer procedure of Example 1, NEt₃ (2.8 mL) andmethanesulfonyl chloride Compound 1i (2.3 g, 20.0 mmol) were added to asolution of morpholin-4-ylamine Compound 11a (2.1 g, 20.0 mmol) in 20 mLof CH₂Cl₂ at 0° C. under a N₂ atmosphere. The mixture was stirred andwarmed to ambient temperature over a 2 hr period, then the reaction wasquenched with water(10 mL). The organic layer was diluted with CH₂Cl₂(60 mL) and washed with water and brine, separated and dried withanhydrous Na₂SO₄, then filtered and concentrated in vacuo to affordN-morpholin-4-yl-methanesulfonamide Compound 11b as an oil.

(Boc)₂O (4.70 g) and DMAP (0.10 g) were added to a solution of CompoundFib in CH₂Cl₂ (30 mL) at O—C under a N₂ atmosphere. The mixture wasstirred and warmed to ambient temperature overnight, then the reactionwas quenched with a saturated solution of NaHCO₃ (20 mL). The organiclayer was diluted with CH₂Cl₂ (60 mL) and washed with water and brine,separated and dried with anhydrous Na₂SO₄, then filtered andconcentrated in vacuo to yield a crude product, which was purified byflash chromatography (eluted with 10% EtOAc in hexane) to affordN-(t-butoxy carbonyl)-N-morpholin-4-yl-methanesulfonamide Compound 11c(4.5 g, 81%) as a white solid.

A 1.0M solution of KOtBu in THF (0.4 mL, 0.4 mmol) was added dropwise toa solution of methanesulfonamide Compound 11c (0.042 g, 0.15 mmol) inanhydrous THF (5 mL) at −78° C. under a N₂ atmosphere. The mixture wasstirred for about 45 min, then carbaldehyde Compound 10c (0.06 g, 0.15mmol) diluted in THF was added dropwise. The mixture was warmed toambient temperature and the reaction was quenched with water. Theorganic layer was diluted with EtOAc and washed with water and brine,separated and dried with anhydrous Na₂SO₄, then filtered andconcentrated in vacuo to yield a crude product, which was purified byflash chromatography to provide Compound 41. MS m/z 551.1 (MH⁺).

EXAMPLE 12(7Z)-[1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl]-piperidin-1-yl-methanone(Cpd 55)

Aqueous KOH (0.3 g in 250 mL water) was added to 4-fluoro-benzaldehydeCompound 12a (4.82 g, 38.9 mmol) and tetrahydro-4H-thiopyran-4-oneCompound 1a (4.5 g, 38.8 mmol), and the mixture was heated to about 65°C. for 24 hrs, then cooled to r.t. and stirred for 2 hrs. The mixturewas acidified to pH 7 with 1.0N HCl (2 mL) and diluted with EtOAc (200mL). The organic layer was separated, washed with brine and dried withanhydrous Na₂SO₄, then filtered and concentrated to provide a crudeproduct, which was purified by silica gel column (eluted with 8% EtOAcin hexane) to give3-(4-fluoro-benzylidene)-tetrahydro-4H-thiopyran-4-one Compound 12b (4.8g, 48.5%) as a white solid.

An oxalic acid di-ethyl ester Compound 12c (1.43 g, 10 mmol) in THF (5mL) was added to a solution of Compound 12b (2.2 g, 10 mmol) in THF (60mL) at 0° C. followed by the dropwise addition of a 1.0M solution ofKOtBu in THF (16.0 mL, 16.0 mmol). The mixture was allowed to warm tor.t. over a 2 hr period, then the reaction was quenched with 1N HCl (2mL). The organic layer was extracted with Et₂O (100 mL) and washed withbrine, separated and dried with anhydrous Na₂SO₄, then filtered andconcentrated in vacuo to yield a[5-(4-fluoro-benzylidene)-4-oxo-tetrahydro-thiopyran-3-yl]-oxo-aceticacid ethyl ester Compound 12d as a brown solid. Compound 12d was used inthe next step without further purification.

2,4-Dichloro-phenyl-hydrazine Compound 12e (1.8 g, 10 mmol) was added toa solution of Compound 12d (3.38 g, 10.1 mmol) in MeOH (60 mL) atambient temperature under a N₂ atmosphere. The mixture was stirredovernight, and 1 mL of concentrated HCl was added. The reaction mixturewas allowed to stir for an additional 6 hrs, concentrated to dryness andthen purified by flash chromatography (eluted with 15% EtOAc in hexane)to afford1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylicacid ethyl ester Compound 12f (2.4 g, 51%) as a solid.

LiOH (1.2 equiv) was added to compound 12f (2.4 g, 5.1 mmol) in a 9:3:1mixture of THF (65 mL), EtOH (21 mL) and water (7 mL). The mixture wasstirred for 24 hrs, acidified to about pH 3 with 1N HCl and extractedwith EtOAc (100 mL). The organic layer was washed with brine and driedover Na₂SO₄, then filtered and concentrated in vacuo to yield Compound12g (2.05 g, 93%) as a white solid.

Thionyl chloride (1.8 g, 15 mmol) was added to a solution of Compound12g (2.0 g) in CH₂Cl₂ at ambient temperature under a N₂ atmosphere. Thereaction was stirred for 12 hrs and concentrated in vacuo to afford anacid chloride Compound 12h.

Compound 12h (0.05 g, 0.10 mmol) was added to a solution of piperidineCompound 12i (0.011 g, 0.11 mmol) in CH₂Cl₂ (5 mL) and TEA (0.14 mL,0.12 mmol). The suspension was stirred at r.t. for 2 hrs, then dilutedwith CH₂Cl₂ (10 mL) and washed with water (10 mL). The organic layer wasdried over Na₂SO₄, then filtered, concentrated and purified on a silicagel column (eluted with 20% EtOAc in hexane) to provide Compound 55.

Using the procedure of Example 12, other compounds that arerepresentative of the invention may be prepared by varying the startingmaterials, reagent(s) and conditions used, such as: Cpd Name MS 11-benzyl-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3- 378 carboxylicacid [(1R)-1-phenyl-ethyl]-amide 191-benzyl-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3- 410 carboxylicacid (1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl)- amide 57(7Z)-[1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)- 4881,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl]-pylrrolidin-1-yl-methanone

EXAMPLE 13(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylicacid piperidin-1-ylamide (Cpd 54)

Compound 12h (0.045 g, 0.10 mmol) was added to a solution of1-amino-piperidine Compound 13a (0.01 g, 0.11 mmol) in CH₂Cl₂ (6 mL) andTEA (0.14 mL, 0.12 mmol). The suspension was stirred at r.t. for 2 hrs,then diluted with CH₂Cl₂ (10 mL) and washed with water (5 mL). Theorganic layer was dried over Na₂SO₄, then concentrated and purified on asilica gel column (eluted with 20% EtOAc in hexane) to provide Compound54 (0.03 g, 58%) as a light yellow solid. MS m/z 517 (MH⁺).

Using the procedure of Example 13, other compounds that arerepresentative of the invention may be prepared by varying the startingmaterials, reagent(s) and conditions used, such as: Cpd Name MS 52(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-595 thiopyrano[4,3-c]pyrazole-3-carboxylic acidN′-(2,4-dichloro-phenyl)- hydrazide 56(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-503 thiopyrano[4,3-c]pyrazole-3-carboxylic acid pyrrolidin-1-ylamide 58(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-566.1 thiopyrano[4,3-c]pyrazole-3-carboxylic acid[(1R,2S)-2-hydroxy-indan-1-yl]- amide 59(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-566 thiopyrano[4,3-c]pyrazole-3-carboxylic acid[(1S,2R)-2-hydroxy-indan-1-yl]- amide 60(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-518 thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1R,2R)-2-hydroxy-cyclopentyl]-amide 61(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-532 thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1R,2R)-2-hydroxy-cyclohexyl]-amide 644-{[(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7- 618.8tetrahydro-thiopyrano[4,3-c]pyrazole-3-carbonyl]-amino}-piperazine-1-carboxylic acid tert-butyl ester 72(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-525.2 thiopyrano[4,3-c]pyrazole-3-carboxylic acid(pyridin-2-ylmethyl)-amide 88(7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-2,4,6,7-tetrahydro-517 thiopyrano[4,3-c]pyrazole-3-carboxylic acid piperidin-1-ylamide 92(7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-2,4,6,7-tetrahydro-543.1 thiopyrano[4,3-c]pyrazole-3-carboxylic acid(hexahydro-cyclopenta[c]pyrrol- 2-yl)-amide 93(7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-483 thiopyrano[4,3-c]pyrazole-3-carboxylic acid piperidin-1-ylamide 102(7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-469 thiopyrano[4,3-c]pyrazole-3-carboxylic acid pyrrolidin-1-ylamide 103(7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-509 thiopyrano[4,3-c]pyrazole-3-carboxylic acid(hexahydro-cyclopenta[c]pyrrol- 2-yl)-amide 111(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-545 thiopyrano[4,3-c]pyrazole-3-carboxylic acid(2,6-dimethyl-piperidin-1-yl)- amide 112(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-531 thiopyrano[4,3-cipyrazole-3-carboxylic acid azepan-1-ylamide 113(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-532 thiopyrano[4,3-c]pyrazole-3-carboxylic acid(4-methyl-piperazin-1-yl)-amide 114(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-562 thiopyrano[4,3-c]pyrazole-3-carboxylic acid[4-(2-hydroxy-ethyl)-piperazin- 1-yl]-amide 115(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-531.1 thiopyrano[4,3-c]pyrazole-3-carboxylic acidN′-cyclohexyl-hydrazide 116(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-543 thiopyrano[4,3-c]pyrazole-3-carboxylic acid(hexahydro-cyclopenta[c]pyrrol- 2-yl)-amide 122(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-548 thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(2R)-2-(methoxymethyl)-pyrrolidin-1-yl]-amide 123(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-546.9 thiopyrano[4,3-c]pyrazole-3-carboxylic acid[(2S)-2-(methoxymethyl)- pyrrolidin-1-yl]-amide 130(7Z)-(4-Bromo-benzylidene)-1-(2,4-dichloro-phenyl)-1,4,6,7-tetrahydro-577 thiopyrano[4,3-c]pyrazole-3-carboxylic acid piperidin-1-ylamide

EXAMPLE 14(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylicacid [(1S)-1-phenyl-ethyl]-amide (Cpd 62)

Compound 12h (0.045 g, 0.1 mmol) was added to a solution of(α¹S)-α-methyl-benzenemethanamine Compound 4a (0.014 g, 0.12 mmol) inCH₂Cl₂ and TEA (0.14 mL, 0.12 mmol). The mixture was stirred at r.t. for2 hrs, then diluted with CH₂Cl₂ (10 mL) and washed with water (5 mL).The organic layer was dried over Na₂SO₄, then concentrated and purifiedon a silica gel column (eluted with 15% EtOAc in hexane) to provideCompound 62 (0.04 g, 74%) as a light yellow solid. MS m/z 538 (MH⁺).

Using the procedure of Example 14, other compounds that arerepresentative of the invention may be prepared by varying the startingmaterials, reagent(s) and conditions used, such as: Cpd Name MS 63(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-538.1 thiopyrano[4,3-c]pyrazole-3-carboxylic acid[(1R)-1-phenyl-ethyl]-amide 78(7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-2,4,6,7-tetrahydro-538 thiopyrano[4,3-c]pyrazole-3-carboxylic acid[(1R)-1-phenyl-ethyl]-amide 89(7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-2,4,6,7-tetrahydro-545.1 thiopyrano[4,3-c]pyrazole-3-carboxylic acid[(1R)-1-cyclohexyl-ethyl]- amide 90(7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-2,4,6,7-tetrahydro-544.2 thiopyrano[4,3-c]pyrazole-3-carboxylic acid [(1S)-1-cyclohexyl-ethyl]amide 91(7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-2,4,6,7-tetrahydro-537 thiopyrano[4,3-c]pyrazole-3-carboxylic acid[(1S)-1-phenyl-ethyl]-amide 94(7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-504.1 thiopyrano[4,3-c]pyrazole-3-carboxylic acid[(1R)-1-phenyl-ethyl]-amide 127(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-539.1 thiopyrano[4,3-c]pyrazole-3-carboxylic acid[(1R)-1-(pyridin-2-yl)-ethyl]- amide 129(7Z)-(4-Bromo-benzylidene)-1-(2,4-dichloro-phenyl)-1,4,6,7-tetrahydro-598 thiopyrano[4,3-c]pyrazole-3-carboxylic acid[(1R)-1-phenyl-ethyl]-amide

Using the methods and procedures from the foregoing Schemes andExamples, other compounds and their equivalents that are representativeof the invention may be prepared by those skilled in the art by varyingthe starting materials, reagent(s) and conditions used.

Additional compounds may be made according to the synthetic methods ofthe present invention by one skilled in the art, differing only inpossible starting materials, reagents and conditions used in the instantmethods.

BIOLOGICAL EXAMPLES

The following examples illustrate that the compounds of the presentinvention are CB receptor modulators useful for treating, amelioratingor preventing a CB receptor mediated syndrome, disorder or disease in asubject in need thereof.

Example 1

Binding Assay for CB1 or CB2 Agonists or Inverse Agonists

The human CB-1 and CB-2 receptors were stably expressed in SK-N-MC cellstransfected with pcDNA3 CB-1 (human) or pcDNA3 CB-2 (human). The cellswere grown in T-180 cell culture flasks under standard cell cultureconditions at 37° C. in a 5% CO₂ atmosphere. The cells were harvested bytrysinization and homogenized in a homogenization buffer (10 mM Tris,0.2 mM MgCl₂, 5 mM KCl, with protease inhibitors aprotinin, leupeptin,pepstatin A and bacitracin) and centrifuged (2000 g). The supernatantwas then centrifuged in 2M sucrose (31300 g) to produce a semi-purifiedmembrane pellet. The pellet was resuspended in homogenization and storeat −80° C.

On the day of the assay, the pellet was thawed on ice and diluted inassay buffer (50 mM Tris-HCl, 5 mM MgCl₂, 2.5 mM EDTA, 0.5 mg/mL fattyacid free bovine serum albumin, pH 7.5). The diluted membrane was addedwith buffer, test compound or standard and the radioligand[H]³⁺-CP-55,940-(0.2 nM) to the wells of a 96-well polypropylene plate.Non-specific binding was measured in wells containing 10 uM WIN 55,212.The plate was covered and incubated for 90 minutes at 30° C. Thecontents were then aspirated onto a Packard Unifilter GF/C filter bottomplate prewet with 0.5% polyethyleneimine. The wells of the polypropyleneplate were rinsed and aspirated seven times with a 0.9% saline-0.5%Tween 20 solution. The Unifilter plate was dried, a scintillationcocktail was added to each well and the counts representing binding werequantitated in a TopCount scintillation counter. CB1 and CB2 ReceptorBinding Results The IC₅₀ binding values for compounds tested werecalculated by linear regression and were obtained from studies in whichvarying compound concentrations were used. Where an IC₅₀ was notobtained, test results are provided as percent inhibition at a testconcentration of ^(a)0.2 μM, ^(b)1 μM or ^(c)10 μM. TABLE 1 CANNABINOIDCB1 RECEPTOR BINDING IC₅₀ (μM) Cpd CB1 IC₅₀ (μM) 1 0.16 2 ^(b)13% 3^(b)23% 4 ^(b)12% 5 ^(b)9% 6 ^(b)16% 7 ^(b)15% 8 ^(b)8% 9 ^(b)6% 10^(b)0% 11 ^(b)29% 12 ^(b)15% 13 ^(b)38% 14 ^(b)0% 15 ^(b)4% 16 ^(b)0% 17^(b)0% 18 ^(b)0% 19 0.005 20 0.022 21 ^(b)53% 22 ^(b)11%, ^(c)0% 25^(c)0%, ^(c)6% 26 ^(c)12%, ^(c)43% 29 ^(c)8% 32 ^(c)35% 33 ^(b)35%,^(c)9% 34 ^(c)11% 35 ^(c)4% 36 ^(b)25.5%, ^(c)1% 37 ^(c)11% 38 ^(a)28%39 ^(a)55% 40 ^(a)12% 41 ^(a)9% 42 ^(a)31% 43 ^(a)41% 44 ^(a)3% 45^(a)33% 46 ^(a)43% 47 ^(a)24% 48 ^(a)15% 49 ^(a)33% 50 ^(a)50% 51^(a)35% 52 ^(a)66% 53 ^(a)55% 54 0.034 55 ^(a)52% 56 0.035 57 ^(a)56% 580.04 59 0.042 60 ^(a)60% 61 ^(a)60% 62 0.048 63 0.009 64 0.024 65 0.00566 0.004 67 ^(a)46% 68 ^(a)52% 69 0.023 70 0.012 71 ^(a)18% 72 ^(a)48%73 ^(a)56% 74 ^(a)45% 75 0.014 76 ^(a)20% 77 ^(a)55% 78 ^(a)62% 79 0.1680 ^(a)21% 81 0.032 82 0.048 83 0.027 84 0.002 85 0.035 86 0.021 870.018 88 ^(a)46% 89 0.074 90 ^(a)31% 91 ^(a)38% 92 ^(a)47% 93 0.036 940.011 95 0.009 96 ^(a)43% 97 0.068 98 ^(a)51% 99 ^(a)66% 100 0.025 101^(a)61% 102 ^(a)76% 103 ^(a)62% 104 ^(a)76% 105 ^(a)50% 106 ^(a)32% 107^(a)92% 108 ^(a)88% 109 ^(a)4% 110 ^(a)13% 111 0.014 112 0.01 113^(a)17% 114 ^(a)6% 115 0.079 116 0.011 117 0.009 118 0.008 119 0.081 1200.033 121 0.048 122 0.006 123 ^(a)61% 124 0.005 125 0.058 126 ^(a)55%127 0.007 128 ^(a)5% 129 0.006 130 0.021

TABLE 2 Cannabinoid CB2 Receptor Binding IC₅₀ (μm) Cpd CB2 IC₅₀ (μM) 10.062 2 ^(b)0% 3 ^(b)74% 4 ^(b)0% 5 ^(b)9% 6 ^(b)0% 7 ^(b)44% 8 ^(b)5% 9^(b)6% 10 ^(b)36% 11 ^(b)39% 12 ^(b)42% 13 ^(b)55% 14 ^(b)0% 15 ^(b)0%16 ^(b)0% 17 ^(b)24% 18 ^(b)40% 19 0.0007 20 0.005 21 0.056 22 ^(b)0%^(c)2% 25 ^(c)23%, ^(c)25%, ^(c)10% 26 ^(c)22%, ^(c)32% 29 ^(c)1%,^(c)32% 32 ^(c)47% 33 6.8 34 ^(c)21% 35 ^(c)28% 36 ^(c)45%, ^(c)3% 37^(c)7% 38 ^(a)15% 39 ^(a)37% 40 ^(a)10% 41 ^(a)8% 42 ^(a)20% 43 ^(a)11%44 ^(a)9% 45 ^(a)8% 46 ^(a)18% 47 ^(a)26% 48 ^(a)11% 49 ^(a)6% 50^(a)24% 51 ^(a)9% 52 ^(a)28% 53 ^(a)30% 54 ^(a)25% 55 ^(a)10% 56 ^(a)15%57 ^(a)21% 58 ^(a)25% 59 ^(a)25% 60 ^(a)17% 61 ^(a)31% 62 ^(a)17% 63^(a)6% 64 ^(a)0% 65 ^(a)17% 66 ^(a)24% 67 ^(a)15% 68 ^(a)19% 69 ^(a)10%70 ^(a)19% 71 ^(a)13% 72 ^(a)10% 73 ^(a)13% 74 ^(a)8% 75 ^(a)2% 76^(a)0% 77 ^(a)9% 78 ^(a)11% 79 ^(a)10% 80 ^(a)2% 81 ^(a)24% 82 ^(a)19%83 ^(a)17% 84 ^(a)17% 85 ^(a)20% 86 ^(a)14% 87 ^(a)4% 88 9% 89 ^(a)10%90 ^(a)18% 91 ^(a)14% 92 ^(a)8% 93 ^(a)26% 94 ^(a)22% 95 ^(a)15% 96^(a)9% 97 ^(a)8% 98 ^(a)14% 99 ^(a)12% 100 ^(a)9% 101 ^(a)24% 102^(a)23% 103 ^(a)5% 104 ^(a)10% 105 ^(a)11% 106 ^(a)6% 107 ^(a)23% 108^(a)18% 109 ^(a)6% 110 ^(a)7% 111 ^(a)16% 112 ^(a)8% 113 ^(a)0% 114^(a)5% 115 ^(a)19% 116 ^(a)18% 117 ^(a)18% 118 ^(a)11% 119 ^(a)17% 120^(a)12% 121 ^(a)15% 122 ^(a)18% 123 ^(a)12% 124 ^(a)12% 125 ^(a)8% 126^(a)0% 127 ^(a)19% 128 ^(a)10% 129 ^(a)26% 130 ^(a)34%

Example 2

Functional Cell-Based Assay for CB1 or CB2 Agonist and Inverse AgonistEffects on Intra-Cellular Adenylate Cyclase Activity

The CB1 and CB2 receptors are G-protein coupled receptors (GPCR), whichinfluence cell function via the Gi-protein. These receptors modulate theactivity of intracellular adenylate cyclase, which in turn produces theintracellular signal messenger cyclic-AMP (cAMP).

At baseline, or during non-ligand bound conditions, these receptors areconstitutively active and tonically suppress adenylate cyclase activity.The binding of an agonist causes further receptor activation andproduces additional suppression of adenylate cyclase activity. Thebinding of an inverse agonist inhibits the constitutive activity of thereceptors and results in an increase in adenylate cyclase activity.

By monitoring intracellular adenylate cyclase activity, the ability ofcompounds to act as agonists or inverse agonists can be determined.

Assay

Test compounds were evaluated in SK-NC cells which, using standardtransfection procedures, were stably transfected with human cDNA forpcDNA3-CRE β-gal and pcDNA3 CB-1 (human) or pcDNA3 CB-2 (human). Byexpressing CRE β-gal, the cells produced β-galactosidasein response toCRE promoter activation by cAMP. Cells expressing CRE 5-gal and eitherthe human CB1 or CB2 receptor will produce less β-galactosidase whentreated with a CB1/CB2 agonist and will produce more β-galactosidasewhen treated with a CB1/CB2 inverse agonist.

Cell Growth

The cells were grown in 96-well plates under standard cell cultureconditions at 37° C. in a 5% CO₂ atmosphere. After 3 days, the media wasremoved and a test compound in media (wherein the media was supplementedwith 2 mM L-glutamine, 1M sodium pyruvate, 0.1% low fatty acid FBS(fetal bovine serum) and antibiotics) was added to the cell. The plateswere incubated for 30 minutes at 37° C. and the plate cells were thentreated with forskolin over a 4-6 hour period, then washed and lysed.The β-galactosidase activity was quantitated using commerciallyavailable kit reagents (Promega Corp. Madison, Wis.) and a Vmax PlateReader (Molecular Devices, Inc).

CB1 Receptor Mediated Change in CRE β-gal Expression

For cells expressing CRE β-gal and the CB1 receptor, CB1 agonistsreduced β-galactosidase activity in a dose-dependent manner and CB1inverse agonists increased β-galactosidase activity in a dose-dependentmanner.

The change in β-galactosidase activity was determined by setting avehicle treated cell's activity value at 100% and expressing theβ-galactosidase activity measured in a corresponding compound treatedcell as a percent of the vehicle treated cell activity.

CB1 Receptor Results

The EC₅₀ and IC₅₀ values for compounds tested were calculated by linearregression and were obtained from studies in which varying compoundconcentrations were used.

CB1 Receptor Functional Results

The EC₅₀ values for compounds tested were calculated by linearregression and were obtained from studies in which varying compoundconcentrations were used. Where an EC₅₀ was not obtained, test resultsare provided as percent inhibition at a test concentration of 1 μM.^(a)Test value in IC₅₀; indicates agonist activity. TABLE 3 CB1 RECEPTORFUNCTIONAL EC₅₀ (μM) Cpd CB1 EC₅₀ (μM) 1 0.07^(a) 3 17% 13 7.88 190.03^(a) 20 0.06^(a) 21 6.3^(a) 25 1% 33 24%

Example 4

Acute Treatment (Ob/Ob Mice)

The effect of acute, single-dose administration of a compound of thepresent invention was tested in hyperphagic obese ob/ob mice. Animalswere orally administered (gavage) either test compound or vehicle. Bodyweight, plasma triglycerides and plasma glucose were monitored.

Animals administered a test compound had a relatively dose-dependentdecrease in body weight, plasma triglycerides and plasma glucosecompared to animals administered vehicle.

It is to be understood that the preceding description teaches theprinciples of the present invention, with examples that have emphasizedcertain aspects. It will also be understood that the practice of theinvention encompasses all of the usual variations, adaptations andmodifications as come within the scope of the following claims and theirequivalents. However, numerous other equivalents not specificallyelaborated on or discussed may nevertheless fall within the spirit andscope of the present invention and claims and are intended to beincluded.

Throughout this application, various publications are cited. Thedisclosure of these publications is hereby incorporated by referenceinto this application to describe more fully the state of the art towhich this invention pertains.

1. A compound of Formula (I)

wherein the dashed lines between positions 2-3 and positions 3a-7a inFormula (I) each represent the location for a double bond when X₁R₁ ispresent; the dashed lines between positions 3-3a and positions 7a-1 inFormula (I) each represent the location for a double bond when X₂R₂ ispresent; the dashed line between position 7 and X₄R₄ in Formula (I)represents the location for a double bond; X is sulfur, sulfoxo orsulfonyl; X₁ is absent or is lower alkylene; X₂ is absent or is loweralkylene; wherein only one of X₁X₁ and X₂R₂ are present; X₃ is absent oris lower alkylene or lower alkylidene; when the dashed line betweenposition 7 and X₄R₄ is absent, then X₄ is absent or is lower alkylene;when the dashed line between position 7 and X₄R₄ is present, then X₄ isabsent; R₁ is hydrogen, aryl, C₃-C₁₂ cycloalkyl, or heterocyclyl,wherein each of aryl, C₃-C₁₂ cycloalkyl, or heterocyclyl is optionallysubstituted at one or more positions by halogen, lower alkyl, hydroxy orlower alkoxy; R₂ is hydrogen, aryl, C₃-C₁₂ cycloalkyl, or heterocyclyl,wherein each of aryl, C₃-C₁₂ cycloalkyl, or heterocyclyl is optionallysubstituted at one or more positions by halogen, lower alkyl, hydroxy orlower alkoxy; R₃ is —C(O)-heterocyclyl or -Z-N(R₆)-Z₁R₇ (optionallysubstituted on heterocyclyl by one or more hydroxy, halogen, amino,lower alkyl, carboxy, alkoxycarbonyl, lower alkoxy, lower alkoxy-loweralkylene-, hydroxy-alkylene-, aryloxy or arylalkoxy); when the dashedline between position 7 and X₄R₄ is absent, then R₄ is hydrogen,hydroxy, lower alkyl, lower alkoxy, halogen, aryl (optionallysubstituted on aryl at one or more positions by hydroxy, lower alkyl,lower alkoxy or halogeno, heterocyclyl (optionally substituted onheterocyclyl at one or more positions by hydroxy, lower alkyl, loweralkoxy or halogen) or C₃-C₁₂ cycloalkyl (optionally substituted onC₃-C₁₂ cycloalkyl at one or more positions by hydroxy, lower alkyl,lower alkoxy or halogen); when the dashed line between position 7 andX₄R₄ is present, then R₄ is CH-aryl (optionally substituted on aryl atone or more positions by hydroxy, lower alkyl, lower alkoxy or halogen)or CH-heterocyclyl (optionally substituted on heterocyclyl at one ormore positions by hydroxy, lower alkyl, lower alkoxy or halogen); R₆ andR₇ are each individually hydrogen, lower alkyl, —NR₈R₉, aryl (optionallysubstituted on aryl by one or more hydroxy, halogen, lower alkyl,carboxy, alkoxycarbonyl, lower alkoxy, hydroxy-alkylene-, aryloxy orarylalkoxy), C₃-C₁₂ cycloalkyl (optionally substituted on C₃-C₁₂cycloalkyl by one or more hydroxy, halogen, amino, lower alkyl, carboxy,alkoxycarbonyl, lower alkoxy, hydroxy-alkylene-, aryloxy, arylalkoxy orlower alkylene) or heterocyclyl (optionally substituted on heterocyclylby one or more hydroxy, halogen, amino, lower alkyl, carboxy,alkoxycarbonyl, lower alkoxy, lower alkoxy-lower alkylene-,hydroxy-alkylene-, aryloxy or arylalkoxy); R₈ and R₉ are eachindividually hydrogen, alkyl, heterocyclyl, C₃-C₁₂ cycloalkyl, or aryl(optionally substituted on aryl by one or more lower alkyl, hydroxy,alkoxy, halogen, heterocyclyl or aryl-lower alkylene-); Z is carbonyl orsulfonyl; Z₁ is absent; or is lower alkylene optionally substituted atone or more positions by halogen, hydroxy, lower alkoxy, carboxy orlower alkoxycarbonyl; or a pharmaceutically acceptable salt, isomer,prodrug, metabolite or polymorph thereof.
 2. The compound of claim 1,wherein X₁ is absent or is lower alkylene and R₁ is hydrogen, C₃-C₁₂cycloalkyl or aryl (optionally substituted on aryl at one or morepositions by lower alkyl, lower alkoxy or halogen).
 3. The compound ofclaim 1, wherein when the dashed line between position 7 and X₄R₄ isabsent, then X₄ is absent or is lower alkylene and R₄ is hydrogen,hydroxy, lower alkyl, lower alkoxy, halogen, aryl (optionallysubstituted on aryl at one or more positions by lower alkoxy orhalogen), heterocyclyl (optionally substituted on heterocyclyl at one ormore positions by halogen) or C₃-C₈ cycloalkyl.
 4. The compound of claim1, wherein when the dashed line between positions 7 and X₄R₄ is absentthen X₄ is absent and R₄ is hydrogen.
 5. The compound of claim 1,wherein X₃ is absent or is lower alkylidene; R₃ is —C(O)-heterocyclyl or-Z-N(R₆)-Z₁R₇ (optionally substituted on heterocyclyl by one or morehydroxy, halogen, amino, lower alkyl, carboxy, alkoxycarbonyl, loweralkoxy, lower alkoxy-lower alkylene-, hydroxy-alkylene-, aryloxy orarylalkoxy); Z is carbonyl or sulfonyl; Z₁ is absent or is loweralkylene; and R₆ and R₇ are each individually hydrogen, lower alkyl,—NR₈R₉, aryl (optionally substituted on aryl by one or more hydroxy,halogen, lower alkyl, carboxy, alkoxycarbonyl, lower alkoxy,hydroxy-alkylene-, aryloxy or arylalkoxy), C₃-C₁₂ cycloalkyl (optionallysubstituted on C₃-C₁₂ cycloalkyl by one or more hydroxy, halogen, amino,lower alkyl, carboxy, alkoxycarbonyl, lower alkoxy, hydroxy-alkylene-,aryloxy, arylalkoxy or lower alkylene) or heterocyclyl (optionallysubstituted on heterocyclyl by one or more hydroxy, halogen, amino,lower alkyl, carboxy, alkoxycarbonyl, lower alkoxy, lower alkoxy-loweralkylene-, hydroxy-alkylene-, aryloxy or arylalkoxy), wherein R₈ and R₉are each individually hydrogen, alkyl, heterocyclyl, C₃-C₁₂ cycloalkylor aryl (optionally substituted on aryl by one or more lower alkyl,hydroxy, alkoxy, halogen, heterocyclyl or aryl-lower alkylene-).
 6. Thecompound of claim 1, wherein X₃ is absent or is lower alkylidene; R₃ is—C(O)-heterocyclyl or -Z-N(R₆)-Z₁R₇; Z is carbonyl or sulfonyl; Z₁ isabsent or is lower alkylene; and R₆ and R₇ are each individuallyhydrogen, lower alkyl, —NR₈R₉, aryl (optionally substituted on aryl byone or more hydroxy, halogen, lower alkyl, lower alkoxy orhydroxy-alkylene-); C₃-C₁₂ cycloalkyl (optionally substituted on C₃-C₁₂cycloalkyl by one or more hydroxy, halogen, amino, lower alkyl, carboxy,alkoxycarbonyl, lower alkoxy or hydroxy-alkylene-) or heterocyclyl(optionally substituted on heterocyclyl by one or more hydroxy, halogen,amino, lower alkyl, carboxy, alkoxycarbonyl, lower alkoxy, loweralkoxy-lower alkylene- or hydroxy-alkylene-), wherein R₈ and R₉ are eachindividually hydrogen, alkyl, heterocyclyl, C₃-C₁₂ cycloalkyl or aryl(optionally substituted on aryl by one or more lower alkyl, hydroxy,alkoxy or halogen).
 7. The compound of claim 1, wherein X₃ is absent oris lower alkylidene; R₃ is —C(O)-heterocyclyl or -Z-N(R₆)-Z₁R₇; Z iscarbonyl or sulfonyl; Z₁ is absent or is lower alkylene; and R₆ and R₇are each individually hydrogen, lower alkyl, —NR₈R , aryl, C₃-C₁₂cycloalkyl (optionally substituted on C₃-C₁₂ cycloalkyl by one or morehydroxy, lower alkyl or alkoxycarbonyl) or heterocyclyl (optionallysubstituted on heterocyclyl by one or more lower alkyl, alkoxycarbonyl,lower alkoxy-lower alkylene- or hydroxy-alkylene-), wherein R₈ and R₉are each individually hydrogen, alkyl, C₃-C₁₂ cycloalkyl or aryl(optionally substituted on aryl by one or more halogen).
 8. The compoundof claim 1, wherein X₂ is absent or is lower alkylene; and, R₂ is C₃-C₁₂cycloalkyl or aryl (optionally substituted on aryl at one or morepositions by lower alkyl, lower alkoxy or halogen).
 9. The compound ofclaim 1, wherein when the dashed line between position 7 and X₄R ispresent, then X₄ is absent and R₄ is CH-aryl (optionally substituted onaryl at one or more positions by hydroxy, lower alkyl, lower alkoxy orhalogen) or CH-heterocyclyl (optionally substituted on heterocyclyl atone or more positions by hydroxy, lower alkyl, lower alkoxy or halogen).10. The compound of claim 1, wherein when the dashed line betweenposition 7 and X₄R₄ is present, then X₄ is absent and R₄ is CH-aryl(optionally substituted on aryl at one or more positions by lower alkyl,lower alkoxy or halogen) or CH-heterocyclyl (optionally substituted onheterocyclyl at one or more positions by lower alkyl, lower alkoxy orhalogen).
 11. The compound of claim 1, wherein when the dashed linebetween position 7 and X₄R₄ is present, then X₄ is absent and R₄ isCH-phenyl, CH-thienyl or CH-furyl (optionally substituted on phenyl,thienyl or furyl at one or more positions by lower alkyl, lower alkoxyor halogen).
 12. The compound of claim 1, wherein X is sulfur, sulfoxoor sulfonyl; X₁ is absent or is lower alkylene; R₁ is hydrogen, C₃-C₁₂cycloalkyl or aryl (optionally substituted on aryl at one or morepositions by lower alkyl, lower alkoxy or halogen); when the dashed linebetween positions 7 and X₄R₄ is absent, then X₄ is absent and R₄ ishydrogen; X₃ is absent or is lower alkylidene; R₃ is —C(O)-heterocyclylor -Z-N(R₆)-Z₁R₇; Z is carbonyl or sulfonyl; Z₁ is absent or is loweralkylene; R₆ and R₇ are each individually hydrogen, lower alkyl, —NR₈R₉,aryl, C₃-C₁₂ cycloalkyl (optionally substituted on C₃-C₁₂ cycloalkyl byone or more hydroxy, lower alkyl or alkoxycarbonyl) or heterocyclyl(optionally substituted on heterocyclyl by one or more lower alkyl,alkoxycarbonyl, lower alkoxy-lower alkylene- or hydroxy-alkylene-),wherein R₈ and R₉ are each individually hydrogen, alkyl, C₃-C₁₂cycloalkyl or aryl (optionally substituted on aryl by one or morehalogen); X₂ is absent or is lower alkylene; R₂ is C₃-C₁₂ cycloalkyl oraryl (optionally substituted on aryl at one or more positions by loweralkyl, lower alkoxy or halogen); and, when the dashed line betweenposition 7 and X₄R₄ is present, then X₄ is absent and R₄ is CH-phenyl,CH-thienyl or CH-furyl (optionally substituted on phenyl, thienyl orfuryl at one or more positions by lower alkyl, lower alkoxy or halogen).13. A compound of the formula:


14. A compound selected from the group consisting of:1-benzyl-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic acid[(1R)-1-phenyl-ethyl]-amide,(E)-2-(1-benzyl-1,4,6,7-tetrahydro-thiopyrano[4-3-c]pyrazol-3-yl)-ethenesulfonicacid [(1S)-1-phenyl-ethyl]-amide,1-benzyl-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylicacid [(1R)-1-phenyl-ethyl]-amide,1-benzyl-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylic acid(1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl)-amide,1-benzyl-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylicacid (1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl)-amide,1-benzyl-5-oxo-4,5,6,7-tetrahydro-1H-5λ⁴-thiopyrano[4,3-c]pyrazole-3-carboxylicacid (1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl)-amide,(E)-2-[1-(2,4-difluoro-phenyl)-7-(3-fluoro-benzyl)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl]-ethenesulfonicacid [(1R)-1-cyclohexyl-ethyl]-amide,(2R,3S)-3-{[1-(2,4-difluoro-phenyl)-(7S)-(3-fluoro-benzyl)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carbonyl]-amino}-bicyclo[2.2.1]heptane-2-carboxylicacid ethyl ester,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylicacid N′-(2,4-dichloro-phenyl)-hydrazide,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylicacid N′-(2,4-dichloro-phenyl)-hydrazide,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylicacid piperidin-1-ylamide,(7Z)-[1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl]-piperidin-1-yl-methanone,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylicacid pyrrolidin-1-ylamide,(7Z)-[1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl]-pyrrolidin-1-yl-methanone,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylicacid [(1R,2S)-2-hydroxy-indan-1-yl]-amide,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylicacid [(1S,2R)-2-hydroxy-indan-1-yl]-amide,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylicacid [(1R,2R)-2-hydroxy-cyclopentyl]-amide,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylicacid [(1R,2R)-2-hydroxy-cyclohexyl]-amide,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylicacid [(1S)-1-phenyl-ethyl]-amide,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylicacid [(1R)-1-phenyl-ethyl]-amide,4-{[(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carbonyl]-amino}-piperazine-1-carboxylicacid tert-butyl ester,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylicacid [(1S)-1-phenyl-ethyl]-amide,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylicacid [(1R)-1-phenyl-ethyl]-amide,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acid[(1S,2S)-2-hydroxy-cyclohexyl]-amide,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylicacid [(1R,2S)-2-hydroxy-indan-1-yl]-amide,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acid[(1S,2R)-2-hydroxy-indan-1-yl]-amide,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylicacid (pyridin-2-ylmethyl)-amide,(7Z)-1-(2,4-dihloro-phenyl)-7-(4-fluoro-benzylidene)-5-oxo-4,5,6,7-tetrahydro-1H-5λ⁴-thiopyrano[4,3-c]pyrazole-3-carboxylicacid [(1R)-1-phenyl-ethyl]-amide,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5-oxo-4,5,6,7-tetrahydro-1H-5λ⁴-thiopyrano[4,3-c]pyrazole-3-carboxylicacid N′-(2,4-dichloro-phenyl)-hydrazide,(7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-2,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylicacid [(1R)-1-phenyl-ethyl]-amide,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5-oxo-4,5,6,7-tetrahydro-1H-5X⁴-thiopyrano[4,3-c]pyrazole-3-carboxylicacid piperidin-1-ylamide,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-14,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylicacid piperidin-1-ylamide,(7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-2H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylicacid [(1R)-1-phenyl-ethyl]-amide,(7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-2H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylicacid piperidin-1-ylamide,(7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-2H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylicacid [(1R)-cyclohexyl-ethyl]-amide,(7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-2H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylicacid [(1S)-1-cyclohexyl-ethyl]-amide,(7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-2H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylicacid [(1S)-1-phenyl-ethyl]-amide,(7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-2H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylicacid (hexahydro-cyclopenta[c]pyrrol-2-yl)-amide,(7Z)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-2,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylicacid [(1R)-1-cyclohexyl-ethyl]-amide,(7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylicacid piperidin-1-ylamide,(7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylicacid [(1R)-1-phenyl-ethyl]-amide,(7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylicacid [(1R)-1-phenyl-ethyl]-amide,(7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-14,5,6,7-tetrahydro1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acid(hexahydro-cyclopenta[c]pyrrol-2-yl)-amide, (7Z)-[1(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-14,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazol-3-yl]-piperidin-1-yl-methanone,(7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylicacid piperidin-1-ylamide,(7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylicacid N′-methyl-N′-phenyl-hydrazide,(7Z)-[1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazol-3-yl]-piperidin-1-yl-methanone,(7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylicacid pyrrolidin-1-ylamide,(7Z)-1-(4-chloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylicacid (hexahydro-cyclopenta[c]pyrrol-2-yl)-amide,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acid(hexahydro-cyclopenta[c]pyrrol-2-yl)-amide,(7Z)-1-(2,4-difluoro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylicacid (hexahydro-cyclopenta[c]pyrrol-2-yl)-amide,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acid azepan-1-ylamide,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acid(2,6-dimethyl-piperidin-1-yl)-amide,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylicacid (2,6-dimethyl-piperidin-1-yl)-amide,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylicacid azepan-1-ylamide,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylicacid N′-cyclohexyl-hydrazide,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylicacid (hexahydro-cyclopenta[c]pyrrol-2-yl)-amide,(7Z)-7-(5-chloro-furan-2-ylmethylene)-1-(2,4-dichloro-phenyl)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylicacid [(1R)-1-phenyl-ethyl]-amide,(7Z)-7-(5-chloro-furan-2-ylmethylene)-1-(2,4-dichloro-phenyl)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylicacid [(1R)-1-cyclohexyl-ethyl]-amide,(7Z)-7-(5-chloro-furan-2-ylmethylene)-1-(2,4-dichloro-phenyl)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylicacid piperidin-1-ylamide,(7Z)-7-(5-chloro-furan-2-ylmethylene)-1-(2,4-dichloro-phenyl)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylicacid azepan-1-ylamide,(7Z)-7-(5-chloro-furan-2-ylmethylene)-1-(2,4-dichloro-phenyl)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylicacid (hexahydro-cyclopenta[c]pyrrol-2-yl)-amide,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylicacid [(2R)-2-(methoxymethyl)-pyrrolidin-1-yl]-amide,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylicacid [(2S)-2-(methoxymethyl)-pyrrolidin-1-yl]-amide,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylicacid [(1R)-1-(pyridin-2-yl)-ethyl]-amide,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-4,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylic acid[(2S)-2-(methoxymethyl)-pyrrolidin-1-yl]-amide,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-5,5-dioxo-14,5,6,7-tetrahydro-1H-5λ⁶-thiopyrano[4,3-c]pyrazole-3-carboxylicacid [(2R)-2-(methoxymethyl)-pyrrolidin-1-yl]-amide,(7Z)-1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylicacid [(1R)-1-(pyridin-2-yl)-ethyl]-amide,(7Z)-(4-Bromo-benzylidene)-1-(2,4-dichloro-phenyl)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylicacid [(1R)-1-phenyl-ethyl]-amide, and(7Z)-(4-Bromo-benzylidene)-1-(2,4-dichloro-phenyl)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-3-carboxylicacid piperidin-1-ylamide.
 15. Use of the compound of claim 1 for themanufacture of a medicament for preventing, treating or ameliorating aCCR2 mediated inflammatory syndrome, disorder or disease.
 16. Use of thecompound of claim 14 for the manufacture of a medicament for preventing,treating or ameliorating a CCR2 mediated inflammatory syndrome, disorderor disease.
 17. A method for treating, ameliorating or preventing acannabinoid receptor mediated syndrome, disorder or disease in a subjectin need thereof comprising the step of administering to the subject aneffective amount of a compound of claim
 1. 18. The method of claim 17wherein the cannabinoid receptor is a CB1 or CB2 receptor; and, thecompound of claim 1 is an agonist, antagonist or inverse-agonist of thereceptor.
 19. The method of claim 17 wherein the syndrome, disorder ordisease is related to appetite, metabolism, diabetes,glaucoma-associated intraocular pressure; social and mood disorders,seizures, substance abuse, learning, cognition or memory, organcontraction or muscle spasm, bowel disorders, respiratory disorders,locomotor activity or movement disorders, immune and inflammationdisorders, unregulated cell growth, pain management or neuroprotection.20. The method of claim 17 wherein the effective amount of the compoundof claim 1 is from about 0.001 mg/kg/day to about 300 mg/kg/day.
 21. Themethod of claim 20, wherein the compound is a compound of claim
 14. 22.The method of claim 21, wherein the effective amount is from about 0.001mg/kg/day to about 300 mg/kg/day.
 23. The method of claim 17 furthercomprising treating, ameliorating or preventing a CB1 receptorinverse-agonist mediated appetite related, obesity related or metabolismrelated syndrome, disorder or disease in a subject in need thereofcomprising the step of administering to the subject an effective amountof a CB1 inverse-agonist compound of claim
 1. 24. The method of claim 23wherein the effective amount of the compound of claim 1 is from about0.001 mg/kg/day to about 300 mg/kg/day.
 25. The method of claim 17further comprising the step of administering to the subject acombination product and/or therapy comprising an effective amount of acompound of claim 1 and a therapeutic agent.
 26. The method of claim 25wherein the therapeutic agent is an anticonvulsant or a contraceptiveagent.
 27. The method of claim 26 wherein the anticonvulsant istopiramate, analogs of topiramate, carbamazepine, valproic acid,lamotrigine, gabapentin, phenytoin and the like and mixtures orpharmaceutically acceptable salts thereof.
 28. The method of claim 26wherein the contraceptive agent is a progestin-only contraceptive, acontraceptive having a progestin component and an estrogen component, oran oral contraceptive optionally having a folic acid component.
 29. Amethod of contraception in a subject comprising the step ofadministering to the subject a composition, wherein the compositioncomprises a contraceptive and a CB1 receptor inverse-agonist orantagonist compound of claim 1, wherein the composition reduces the urgeto smoke in the subject and/or assists the subject in losing weight.